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7902317 | An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A. | Metachromatic leukodystrophy (MLD) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme arylsulfatase A (ASA). We have identified a new mutation in the ASA gene of a patient with adult-type MLD. In this mutation, the glycine at position 122, a highly conserved residue in the AS gene family, was replaced by serine. In a transient expression study, COS cells transfected with the mutant cDNA carrying 122Gly-->Ser did not show an increase of ASA activity and produced little material immunoreactive to an anti-ASA antibody, despite normal mRNA levels. | An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in /"arylsulfatase A"/. | Metachromatic leukodystrophy (MLD) is a /"lysosomal storage disease"/ with autosomal recessive inheritance caused by a deficiency of the enzyme /"arylsulfatase A"/ (ASA). We have identified a new mutation in the ASA gene of a patient with adult-type MLD. In this mutation, the glycine at position 122, a highly conserved residue in the AS gene family, was replaced by serine. In a transient expression study, COS cells transfected with the mutant cDNA carrying 122Gly-->Ser did not show an increase of ASA activity and produced little material immunoreactive to an anti-ASA antibody, despite normal mRNA levels. | [
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"text_name": "arylsulfatase A"
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"entity_id": "410",
"entity_type": "Gene",
"text_name": "arylsulfatase A"
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"entity_id": "D016464",
"entity_type": "Disease",
"text_name": "lysosomal storage disease"
} | No |
7981680 | Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors. | Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and the allele inherited from the mother is inactive in most normal tissues. IGF-II expression is activated in several types of human neoplasms and an alteration of IGF-II imprinting has been described in Beckwith-Wiedemann syndrome and Wilms' tumor. Here we show that monoallelic expression of IGF-II gene is conserved in normal adult muscle tissue whereas two or more copies of active IGF-II alleles, arising by either relaxation of imprinting or duplication of the active allele, are found in 9 out of 11 (82%) rhabdomyosarcomas retaining heterozygosity at 11p15, regardless of the histological subtype. Since IGF-II has been indicated as an autocrine growth factor for rhabdomyosarcoma cells, these findings strongly suggest that acquisition of a double dosage of active IGF-II gene is an important step for the initiation or progression of rhabdomyosarcoma tumorigenesis. Among different types of muscle tumors, relaxation of imprinting seems to arise prevalently in rhabdomyosarcomas, since we have detected only one case of partial reactivation of the maternal IGF-II allele out of 7 leiomyosarcomas tested. | Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors. | /"Insulin-like growth factor II (IGF-II"/) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. /"IGF-II"/ gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and the allele inherited from the mother is inactive in most normal tissues. /"IGF-II"/ expression is activated in several types of human neoplasms and an alteration of /"IGF-II"/ imprinting has been described in Beckwith-Wiedemann syndrome and Wilms' tumor. Here we show that monoallelic expression of /"IGF-II"/ gene is conserved in normal adult muscle tissue whereas two or more copies of active /"IGF-II"/ alleles, arising by either relaxation of imprinting or duplication of the active allele, are found in 9 out of 11 (82%) /"rhabdomyosarcomas"/ retaining heterozygosity at 11p15, regardless of the histological subtype. Since /"IGF-II"/ has been indicated as an autocrine growth factor for /"rhabdomyosarcoma"/ cells, these findings strongly suggest that acquisition of a double dosage of active /"IGF-II"/ gene is an important step for the initiation or progression of /"rhabdomyosarcoma tumorigenesis"/. Among different types of muscle tumors, relaxation of imprinting seems to arise prevalently in /"rhabdomyosarcomas"/, since we have detected only one case of partial reactivation of the maternal /"IGF-II"/ allele out of 7 leiomyosarcomas tested. | [
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"entity_id": "D012208",
"entity_type": "Disease",
"text_name": "rhabdomyosarcoma tumorigenesis"
} | Yes |
7981680 | Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors. | Insulin-like growth factor II (IGF-II) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. IGF-II gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and the allele inherited from the mother is inactive in most normal tissues. IGF-II expression is activated in several types of human neoplasms and an alteration of IGF-II imprinting has been described in Beckwith-Wiedemann syndrome and Wilms' tumor. Here we show that monoallelic expression of IGF-II gene is conserved in normal adult muscle tissue whereas two or more copies of active IGF-II alleles, arising by either relaxation of imprinting or duplication of the active allele, are found in 9 out of 11 (82%) rhabdomyosarcomas retaining heterozygosity at 11p15, regardless of the histological subtype. Since IGF-II has been indicated as an autocrine growth factor for rhabdomyosarcoma cells, these findings strongly suggest that acquisition of a double dosage of active IGF-II gene is an important step for the initiation or progression of rhabdomyosarcoma tumorigenesis. Among different types of muscle tumors, relaxation of imprinting seems to arise prevalently in rhabdomyosarcomas, since we have detected only one case of partial reactivation of the maternal IGF-II allele out of 7 leiomyosarcomas tested. | Mono- and bi-allelic expression of insulin-like growth factor II gene in human muscle tumors. | /"Insulin-like growth factor II (IGF-II"/) is a mitogen for many cell types and an important modulator of muscle growth and differentiation. /"IGF-II"/ gene is prevalently expressed during prenatal development and its gene activity is regulated by genomic imprinting, in that the allele inherited from the father is active and the allele inherited from the mother is inactive in most normal tissues. /"IGF-II"/ expression is activated in several types of human /"neoplasms"/ and an alteration of /"IGF-II"/ imprinting has been described in Beckwith-Wiedemann syndrome and Wilms' tumor. Here we show that monoallelic expression of /"IGF-II"/ gene is conserved in normal adult muscle tissue whereas two or more copies of active /"IGF-II"/ alleles, arising by either relaxation of imprinting or duplication of the active allele, are found in 9 out of 11 (82%) rhabdomyosarcomas retaining heterozygosity at 11p15, regardless of the histological subtype. Since /"IGF-II"/ has been indicated as an autocrine growth factor for rhabdomyosarcoma cells, these findings strongly suggest that acquisition of a double dosage of active /"IGF-II"/ gene is an important step for the initiation or progression of rhabdomyosarcoma tumorigenesis. Among different types of muscle tumors, relaxation of imprinting seems to arise prevalently in rhabdomyosarcomas, since we have detected only one case of partial reactivation of the maternal /"IGF-II"/ allele out of 7 leiomyosarcomas tested. | [
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} | No |
7987717 | [The molecular basis of HLA DR4 alleles associated with rheumatoid arthritis in a Chinese population]. | HLA-DR4 gene was studied by polymerase chain reaction method in 95 patients with rheumatoid arthritis(RA) and 130 normal controls in a Shanghai population. The results showed that the DR4 was significantly associated with RA(RR = 3.1, chi 2 = 13.8, P < 0.005). The second exon of DR4 gene was also analysed by PCR-RFLP technique. There were at lest eight DR4 subtypes in this Chinese population. The DRB1 *0405 (Dw15) was the most common allele, accounting for 48% of DR4 positive normal individuals and also is a principal subtype associated with RA susceptibility (RR = 3.1, P < 0.005). Analysis of the third hyperpolymorphic region of DR4 positive samples showed that 92% of patients had a sequence encoding amino acids RRAA or KRAA compared with 56% of the DR4 positive controls (chi 2 = 10.29 P < 0.005). All subtypes that were positively associated with RA susceptibility had the RRAA (DRB1* 0404, 0405. 0408 and 0410) or KRAA (DRB1 * 0401) sequences, while the negatively associated ones (DRB1 0402, 0403 and 0406) had not. As a further evidence, it strongly supported the "shared epitope" hypothesis. The different DR4 subtype structures and frequencies may account for the different associations of DR4 with RA in various ethnic groups. | [The molecular basis of HLA DR4 alleles associated with /"rheumatoid arthritis"/ in a Chinese population]. | HLA-DR4 gene was studied by polymerase chain reaction method in 95 patients with /"rheumatoid arthritis"/(/"RA"/) and 130 normal controls in a Shanghai population. The results showed that the DR4 was significantly associated with /"RA"/(RR = 3.1, chi 2 = 13.8, P < 0.005). The second exon of DR4 gene was also analysed by PCR-RFLP technique. There were at lest eight DR4 subtypes in this Chinese population. The /"DRB1"/ *0405 (Dw15) was the most common allele, accounting for 48% of DR4 positive normal individuals and also is a principal subtype associated with /"RA"/ susceptibility (RR = 3.1, P < 0.005). Analysis of the third hyperpolymorphic region of DR4 positive samples showed that 92% of patients had a sequence encoding amino acids RRAA or KRAA compared with 56% of the DR4 positive controls (chi 2 = 10.29 P < 0.005). All subtypes that were positively associated with /"RA"/ susceptibility had the RRAA (/"DRB1"/* 0404, 0405. 0408 and 0410) or KRAA (/"DRB1"/ * 0401) sequences, while the negatively associated ones (/"DRB1"/ 0402, 0403 and 0406) had not. As a further evidence, it strongly supported the "shared epitope" hypothesis. The different DR4 subtype structures and frequencies may account for the different associations of DR4 with /"RA"/ in various ethnic groups. | [
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] | {
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"text_name": "rheumatoid arthritis"
} | Yes |
7987717 | [The molecular basis of HLA DR4 alleles associated with rheumatoid arthritis in a Chinese population]. | HLA-DR4 gene was studied by polymerase chain reaction method in 95 patients with rheumatoid arthritis(RA) and 130 normal controls in a Shanghai population. The results showed that the DR4 was significantly associated with RA(RR = 3.1, chi 2 = 13.8, P < 0.005). The second exon of DR4 gene was also analysed by PCR-RFLP technique. There were at lest eight DR4 subtypes in this Chinese population. The DRB1 *0405 (Dw15) was the most common allele, accounting for 48% of DR4 positive normal individuals and also is a principal subtype associated with RA susceptibility (RR = 3.1, P < 0.005). Analysis of the third hyperpolymorphic region of DR4 positive samples showed that 92% of patients had a sequence encoding amino acids RRAA or KRAA compared with 56% of the DR4 positive controls (chi 2 = 10.29 P < 0.005). All subtypes that were positively associated with RA susceptibility had the RRAA (DRB1* 0404, 0405. 0408 and 0410) or KRAA (DRB1 * 0401) sequences, while the negatively associated ones (DRB1 0402, 0403 and 0406) had not. As a further evidence, it strongly supported the "shared epitope" hypothesis. The different DR4 subtype structures and frequencies may account for the different associations of DR4 with RA in various ethnic groups. | [The molecular basis of HLA /"DR4"/ alleles associated with /"rheumatoid arthritis"/ in a Chinese population]. | HLA-/"DR4"/ gene was studied by polymerase chain reaction method in 95 patients with /"rheumatoid arthritis"/(/"RA"/) and 130 normal controls in a Shanghai population. The results showed that the /"DR4"/ was significantly associated with /"RA"/(RR = 3.1, chi 2 = 13.8, P < 0.005). The second exon of /"DR4"/ gene was also analysed by PCR-RFLP technique. There were at lest eight /"DR4"/ subtypes in this Chinese population. The DRB1 *0405 (Dw15) was the most common allele, accounting for 48% of /"DR4"/ positive normal individuals and also is a principal subtype associated with /"RA"/ susceptibility (RR = 3.1, P < 0.005). Analysis of the third hyperpolymorphic region of /"DR4"/ positive samples showed that 92% of patients had a sequence encoding amino acids RRAA or KRAA compared with 56% of the /"DR4"/ positive controls (chi 2 = 10.29 P < 0.005). All subtypes that were positively associated with /"RA"/ susceptibility had the RRAA (DRB1* 0404, 0405. 0408 and 0410) or KRAA (DRB1 * 0401) sequences, while the negatively associated ones (DRB1 0402, 0403 and 0406) had not. As a further evidence, it strongly supported the "shared epitope" hypothesis. The different /"DR4"/ subtype structures and frequencies may account for the different associations of /"DR4"/ with /"RA"/ in various ethnic groups. | [
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8000303 | Genetics of CYP1A1: coamplification of specific alleles by polymerase chain reaction and association with breast cancer. | CYP1A1 is a gene of the cytochrome P-450 family that has been proposed to be a biomarker of cancer risk. We introduce a polymerase chain reaction-based assay to measure allelic variability in exon 7 of the CYP1A1 gene. This genetic variant is associated with an amino acid change at residue 462 in the aryl hydrocarbon hydroxylase protein product. Previously, measurement of CYP1A1 genotypes at this variant site required two assays, one to detect each allele. By using three primers in a single polymerase chain reaction rather than two primers in each of two polymerase chain reactions, the proposed assay may facilitate population-based study protocols. We estimate the frequency of this polymorphism in a Caucasian population to be 0.03, with an observed heterozygosity of 0.06. We have also confirmed the Mendelian segregation of this polymorphism in four multigeneration Centre d'Etude du Polymorphisme Humain families and have placed this locus in a multilocus linkage map on chromosome 15q. The distribution of this polymorphism was the same in breast cancer cases as in two sets of healthy controls. | Genetics of /"CYP1A1"/: coamplification of specific alleles by polymerase chain reaction and association with /"breast cancer"/. | /"CYP1A1"/ is a gene of the cytochrome P-450 family that has been proposed to be a biomarker of cancer risk. We introduce a polymerase chain reaction-based assay to measure allelic variability in exon 7 of the /"CYP1A1"/ gene. This genetic variant is associated with an amino acid change at residue 462 in the /"aryl hydrocarbon hydroxylase"/ protein product. Previously, measurement of /"CYP1A1"/ genotypes at this variant site required two assays, one to detect each allele. By using three primers in a single polymerase chain reaction rather than two primers in each of two polymerase chain reactions, the proposed assay may facilitate population-based study protocols. We estimate the frequency of this polymorphism in a Caucasian population to be 0.03, with an observed heterozygosity of 0.06. We have also confirmed the Mendelian segregation of this polymorphism in four multigeneration Centre d'Etude du Polymorphisme Humain families and have placed this locus in a multilocus linkage map on chromosome 15q. The distribution of this polymorphism was the same in /"breast cancer"/ cases as in two sets of healthy controls. | [
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8000303 | Genetics of CYP1A1: coamplification of specific alleles by polymerase chain reaction and association with breast cancer. | CYP1A1 is a gene of the cytochrome P-450 family that has been proposed to be a biomarker of cancer risk. We introduce a polymerase chain reaction-based assay to measure allelic variability in exon 7 of the CYP1A1 gene. This genetic variant is associated with an amino acid change at residue 462 in the aryl hydrocarbon hydroxylase protein product. Previously, measurement of CYP1A1 genotypes at this variant site required two assays, one to detect each allele. By using three primers in a single polymerase chain reaction rather than two primers in each of two polymerase chain reactions, the proposed assay may facilitate population-based study protocols. We estimate the frequency of this polymorphism in a Caucasian population to be 0.03, with an observed heterozygosity of 0.06. We have also confirmed the Mendelian segregation of this polymorphism in four multigeneration Centre d'Etude du Polymorphisme Humain families and have placed this locus in a multilocus linkage map on chromosome 15q. The distribution of this polymorphism was the same in breast cancer cases as in two sets of healthy controls. | Genetics of /"CYP1A1"/: coamplification of specific alleles by polymerase chain reaction and association with breast cancer. | /"CYP1A1"/ is a gene of the cytochrome P-450 family that has been proposed to be a biomarker of /"cancer"/ risk. We introduce a polymerase chain reaction-based assay to measure allelic variability in exon 7 of the /"CYP1A1"/ gene. This genetic variant is associated with an amino acid change at residue 462 in the /"aryl hydrocarbon hydroxylase"/ protein product. Previously, measurement of /"CYP1A1"/ genotypes at this variant site required two assays, one to detect each allele. By using three primers in a single polymerase chain reaction rather than two primers in each of two polymerase chain reactions, the proposed assay may facilitate population-based study protocols. We estimate the frequency of this polymorphism in a Caucasian population to be 0.03, with an observed heterozygosity of 0.06. We have also confirmed the Mendelian segregation of this polymorphism in four multigeneration Centre d'Etude du Polymorphisme Humain families and have placed this locus in a multilocus linkage map on chromosome 15q. The distribution of this polymorphism was the same in breast cancer cases as in two sets of healthy controls. | [
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8094979 | Association between severity of alcoholism and the A1 allele of the dopamine D2 receptor gene TaqI A RFLP in Japanese. | The allelic association of TaqI A restriction fragment length polymorphism (RFLP) of the dopamine D2 receptor gene with alcoholism was examined in 78 Japanese alcoholics and compared with Japanese controls. A significantly higher frequency of the A1 allele (0.42) was found in 100 Japanese unscreened controls compared with those reported in white populations. Among 70 alcoholics whose severities were determined, the A1 allele was present in 77% of 43 more severe alcoholics and in 59% of 27 less severe alcoholics. The A1 allele was present significantly less frequently in the alcoholics at the age of 60 or older (42%), compared with those under the age of 60 (74%). In the subjects under the age of 60, the A1 allele was present in 83% of the 35 more severe alcoholics, being significantly more frequent than in 60% of the 35 nonalcoholic controls. All of the 7 alcoholics homozygous for the A1 allele were classified as severe. The average severity of alcoholism increased in the order A2/A2, A1/A2, and A1/A1 genotypes. These data suggest that the A1 allele is associated with severe alcoholism in the Japanese population and that the effect is related to or has a linkage disequilibrium with a genetic factor that has a small but not negligible additive effect on alcoholism. | Association between severity of /"alcoholism"/ and the A1 allele of the /"dopamine D2 receptor"/ gene TaqI A RFLP in Japanese. | The allelic association of TaqI A restriction fragment length polymorphism (RFLP) of the /"dopamine D2 receptor"/ gene with /"alcoholism"/ was examined in 78 Japanese alcoholics and compared with Japanese controls. A significantly higher frequency of the A1 allele (0.42) was found in 100 Japanese unscreened controls compared with those reported in white populations. Among 70 alcoholics whose severities were determined, the A1 allele was present in 77% of 43 more severe alcoholics and in 59% of 27 less severe alcoholics. The A1 allele was present significantly less frequently in the alcoholics at the age of 60 or older (42%), compared with those under the age of 60 (74%). In the subjects under the age of 60, the A1 allele was present in 83% of the 35 more severe alcoholics, being significantly more frequent than in 60% of the 35 nonalcoholic controls. All of the 7 alcoholics homozygous for the A1 allele were classified as severe. The average severity of /"alcoholism"/ increased in the order A2/A2, A1/A2, and A1/A1 genotypes. These data suggest that the A1 allele is associated with severe /"alcoholism"/ in the Japanese population and that the effect is related to or has a linkage disequilibrium with a genetic factor that has a small but not negligible additive effect on /"alcoholism"/. | [
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8281141 | Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains. | Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Previously, mutations in the fibrillin-1 gene on chromosome 15 (FBN1) have been reported to cause MFS. We have now screened 44 probands with MFS or related phenotypes for alterations in the entire fibrillin coding sequence (9.3 kb) by single strand conformation analysis. We report four unique mutations in the fibrillin gene of unrelated MFS patients. One is a 17 bp deletion and three are missense mutations, two of which involve 8-cysteine motifs. Another missense mutation was found in two unrelated individuals with annuloaortic ectasia but was also present in unaffected relatives and controls from various ethnic backgrounds. By using allele-specific oligonucleotide hybridization, we screened 65 unrelated MFS patients, 29 patients with related phenotypes and 84 control individuals for these mutations as well as for a previously reported mutation and two polymorphisms. Our results suggest that most MFS families carry unique mutations and that the fibrillin genotype is not the sole determinant of the connective tissue phenotype. | Mutation screening of complete /"fibrillin-1"/ coding sequence: report of five new mutations, including two in 8-cysteine domains. | /"Marfan syndrome"/ (/"MFS"/) is an autosomal dominantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Previously, mutations in the /"fibrillin-1"/ gene on chromosome 15 (/"FBN1"/) have been reported to cause /"MFS"/. We have now screened 44 probands with /"MFS"/ or related phenotypes for alterations in the entire fibrillin coding sequence (9.3 kb) by single strand conformation analysis. We report four unique mutations in the fibrillin gene of unrelated /"MFS"/ patients. One is a 17 bp deletion and three are missense mutations, two of which involve 8-cysteine motifs. Another missense mutation was found in two unrelated individuals with annuloaortic ectasia but was also present in unaffected relatives and controls from various ethnic backgrounds. By using allele-specific oligonucleotide hybridization, we screened 65 unrelated /"MFS"/ patients, 29 patients with related phenotypes and 84 control individuals for these mutations as well as for a previously reported mutation and two polymorphisms. Our results suggest that most /"MFS"/ families carry unique mutations and that the fibrillin genotype is not the sole determinant of the connective tissue phenotype. | [
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8281141 | Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains. | Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Previously, mutations in the fibrillin-1 gene on chromosome 15 (FBN1) have been reported to cause MFS. We have now screened 44 probands with MFS or related phenotypes for alterations in the entire fibrillin coding sequence (9.3 kb) by single strand conformation analysis. We report four unique mutations in the fibrillin gene of unrelated MFS patients. One is a 17 bp deletion and three are missense mutations, two of which involve 8-cysteine motifs. Another missense mutation was found in two unrelated individuals with annuloaortic ectasia but was also present in unaffected relatives and controls from various ethnic backgrounds. By using allele-specific oligonucleotide hybridization, we screened 65 unrelated MFS patients, 29 patients with related phenotypes and 84 control individuals for these mutations as well as for a previously reported mutation and two polymorphisms. Our results suggest that most MFS families carry unique mutations and that the fibrillin genotype is not the sole determinant of the connective tissue phenotype. | Mutation screening of complete /"fibrillin-1"/ coding sequence: report of five new mutations, including two in 8-cysteine domains. | Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder characterized by cardiovascular, ocular and skeletal manifestations. Previously, mutations in the /"fibrillin-1"/ gene on chromosome 15 (/"FBN1"/) have been reported to cause MFS. We have now screened 44 probands with MFS or related phenotypes for alterations in the entire fibrillin coding sequence (9.3 kb) by single strand conformation analysis. We report four unique mutations in the fibrillin gene of unrelated MFS patients. One is a 17 bp deletion and three are missense mutations, two of which involve 8-cysteine motifs. Another missense mutation was found in two unrelated individuals with /"annuloaortic ectasia"/ but was also present in unaffected relatives and controls from various ethnic backgrounds. By using allele-specific oligonucleotide hybridization, we screened 65 unrelated MFS patients, 29 patients with related phenotypes and 84 control individuals for these mutations as well as for a previously reported mutation and two polymorphisms. Our results suggest that most MFS families carry unique mutations and that the fibrillin genotype is not the sole determinant of the connective tissue phenotype. | [
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8627522 | The 5-hydroxytryptamine2B receptor and 5-HT receptor signal transduction in mesenteric arteries from deoxycorticosterone acetate-salt hypertensive rats. | One of the most profound increases in vascular responsiveness in hypertension has been observed for serotonin (5-hydroxytryptamine, 5-HT). This study investigates the hypothesis that the increase in vascular responsiveness to 5-HT is the result of altered 5-HT receptor signal transduction. Mesenteric arteries were dissected from deoxycorticosterone- (DOCA) salt hypertensive and sham-normotensive rats for use in isolated tissue experiments. Agonist contractile potencies indicated that a 5-HT2 receptor mediates contraction to 5-HT in both sham and DOCA-salt arteries. In arteries from sham rats, ketanserin (5-HT2A/5-HT2C selective), LY53857 (5-HT2 selective) and spiperone (5-HT2A/5-HT2C selective) shifted contraction to 5-HT (pKB = 8.58, 8.35 and 9.52, respectively) indicating that a 5-HT2A receptor mediates contraction in arteries from normotensive rats. By contrast, ketanserin and spiperone did not shift contraction to 5-HT in DOCA-salt mesenteric arteries (pKB > 6.52, > 7.52, respectively). LY53857 did shift the response to 5-HT in DOCA-salt mesenteric arteries (pKB = 7.85). Thus, contraction in arteries from DOCA-salt rats is predominantly mediated by 5-HT2B receptors. Unlike the 5-HT receptor in the sham mesenteric artery and aorta (5-HT2A receptor), the 5-HT receptor in DOCA-salt mesenteric arteries and stomach fundus (5-HT2B receptor) were relatively insensitive to phenoxybenzamine (10-300 nM). These data suggest that the 5-HT2B receptor is insensitive to phenoxybenzamine, is increased in number or, alternatively, has increased G protein coupling. DOCA-salt mesenteric arteries were more sensitive to contraction by the direct G protein stimulator AIF4- (-log EC50 [M]: DOCA-salt = 2.82 +/- 0.04; sham = 2.55 +/- 0.03, P < .05). PCR analyses indicated an increase in mRNA for the 5-HT2B receptor in mesenteric arteries of DOCA-salt hypertensive arteries, supporting an increase in receptor number. Taken together these studies demonstrate significant changes in 5-HT receptor signal transduction in DOCA-salt hypertension, both at the level of the receptor and G protein and may provide one reason why ketanserin has proved to be a relatively ineffective antihypertensive agent in some forms of hypertension. | The 5-hydroxytryptamine2B receptor and 5-HT receptor signal transduction in mesenteric arteries from deoxycorticosterone acetate-salt /"hypertensive"/ rats. | One of the most profound increases in vascular responsiveness in /"hypertension"/ has been observed for serotonin (5-hydroxytryptamine, 5-HT). This study investigates the hypothesis that the increase in vascular responsiveness to 5-HT is the result of altered 5-HT receptor signal transduction. Mesenteric arteries were dissected from deoxycorticosterone- (DOCA) salt /"hypertensive"/ and sham-normotensive rats for use in isolated tissue experiments. Agonist contractile potencies indicated that a 5-HT2 receptor mediates contraction to 5-HT in both sham and DOCA-salt arteries. In arteries from sham rats, ketanserin (5-HT2A/5-HT2C selective), LY53857 (5-HT2 selective) and spiperone (5-HT2A/5-HT2C selective) shifted contraction to 5-HT (pKB = 8.58, 8.35 and 9.52, respectively) indicating that a 5-HT2A receptor mediates contraction in arteries from normotensive rats. By contrast, ketanserin and spiperone did not shift contraction to 5-HT in DOCA-salt mesenteric arteries (pKB > 6.52, > 7.52, respectively). LY53857 did shift the response to 5-HT in DOCA-salt mesenteric arteries (pKB = 7.85). Thus, contraction in arteries from DOCA-salt rats is predominantly mediated by /"5-HT2B"/ receptors. Unlike the 5-HT receptor in the sham mesenteric artery and aorta (5-HT2A receptor), the 5-HT receptor in DOCA-salt mesenteric arteries and stomach fundus (/"5-HT2B"/ receptor) were relatively insensitive to phenoxybenzamine (10-300 nM). These data suggest that the /"5-HT2B"/ receptor is insensitive to phenoxybenzamine, is increased in number or, alternatively, has increased G protein coupling. DOCA-salt mesenteric arteries were more sensitive to contraction by the direct G protein stimulator AIF4- (-log EC50 [M]: DOCA-salt = 2.82 +/- 0.04; sham = 2.55 +/- 0.03, P < .05). PCR analyses indicated an increase in mRNA for the /"5-HT2B"/ receptor in mesenteric arteries of DOCA-salt /"hypertensive"/ arteries, supporting an increase in receptor number. Taken together these studies demonstrate significant changes in 5-HT receptor signal transduction in DOCA-salt /"hypertension"/, both at the level of the receptor and G protein and may provide one reason why ketanserin has proved to be a relatively ineffective antihypertensive agent in some forms of /"hypertension"/. | [
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8627522 | The 5-hydroxytryptamine2B receptor and 5-HT receptor signal transduction in mesenteric arteries from deoxycorticosterone acetate-salt hypertensive rats. | One of the most profound increases in vascular responsiveness in hypertension has been observed for serotonin (5-hydroxytryptamine, 5-HT). This study investigates the hypothesis that the increase in vascular responsiveness to 5-HT is the result of altered 5-HT receptor signal transduction. Mesenteric arteries were dissected from deoxycorticosterone- (DOCA) salt hypertensive and sham-normotensive rats for use in isolated tissue experiments. Agonist contractile potencies indicated that a 5-HT2 receptor mediates contraction to 5-HT in both sham and DOCA-salt arteries. In arteries from sham rats, ketanserin (5-HT2A/5-HT2C selective), LY53857 (5-HT2 selective) and spiperone (5-HT2A/5-HT2C selective) shifted contraction to 5-HT (pKB = 8.58, 8.35 and 9.52, respectively) indicating that a 5-HT2A receptor mediates contraction in arteries from normotensive rats. By contrast, ketanserin and spiperone did not shift contraction to 5-HT in DOCA-salt mesenteric arteries (pKB > 6.52, > 7.52, respectively). LY53857 did shift the response to 5-HT in DOCA-salt mesenteric arteries (pKB = 7.85). Thus, contraction in arteries from DOCA-salt rats is predominantly mediated by 5-HT2B receptors. Unlike the 5-HT receptor in the sham mesenteric artery and aorta (5-HT2A receptor), the 5-HT receptor in DOCA-salt mesenteric arteries and stomach fundus (5-HT2B receptor) were relatively insensitive to phenoxybenzamine (10-300 nM). These data suggest that the 5-HT2B receptor is insensitive to phenoxybenzamine, is increased in number or, alternatively, has increased G protein coupling. DOCA-salt mesenteric arteries were more sensitive to contraction by the direct G protein stimulator AIF4- (-log EC50 [M]: DOCA-salt = 2.82 +/- 0.04; sham = 2.55 +/- 0.03, P < .05). PCR analyses indicated an increase in mRNA for the 5-HT2B receptor in mesenteric arteries of DOCA-salt hypertensive arteries, supporting an increase in receptor number. Taken together these studies demonstrate significant changes in 5-HT receptor signal transduction in DOCA-salt hypertension, both at the level of the receptor and G protein and may provide one reason why ketanserin has proved to be a relatively ineffective antihypertensive agent in some forms of hypertension. | The 5-hydroxytryptamine2B receptor and 5-HT receptor signal transduction in mesenteric arteries from deoxycorticosterone acetate-salt /"hypertensive"/ rats. | One of the most profound increases in vascular responsiveness in /"hypertension"/ has been observed for serotonin (5-hydroxytryptamine, 5-HT). This study investigates the hypothesis that the increase in vascular responsiveness to 5-HT is the result of altered 5-HT receptor signal transduction. Mesenteric arteries were dissected from deoxycorticosterone- (DOCA) salt /"hypertensive"/ and sham-normotensive rats for use in isolated tissue experiments. Agonist contractile potencies indicated that a 5-HT2 receptor mediates contraction to 5-HT in both sham and DOCA-salt arteries. In arteries from sham rats, ketanserin (5-HT2A//"5-HT2C"/ selective), LY53857 (5-HT2 selective) and spiperone (5-HT2A//"5-HT2C"/ selective) shifted contraction to 5-HT (pKB = 8.58, 8.35 and 9.52, respectively) indicating that a 5-HT2A receptor mediates contraction in arteries from normotensive rats. By contrast, ketanserin and spiperone did not shift contraction to 5-HT in DOCA-salt mesenteric arteries (pKB > 6.52, > 7.52, respectively). LY53857 did shift the response to 5-HT in DOCA-salt mesenteric arteries (pKB = 7.85). Thus, contraction in arteries from DOCA-salt rats is predominantly mediated by 5-HT2B receptors. Unlike the 5-HT receptor in the sham mesenteric artery and aorta (5-HT2A receptor), the 5-HT receptor in DOCA-salt mesenteric arteries and stomach fundus (5-HT2B receptor) were relatively insensitive to phenoxybenzamine (10-300 nM). These data suggest that the 5-HT2B receptor is insensitive to phenoxybenzamine, is increased in number or, alternatively, has increased G protein coupling. DOCA-salt mesenteric arteries were more sensitive to contraction by the direct G protein stimulator AIF4- (-log EC50 [M]: DOCA-salt = 2.82 +/- 0.04; sham = 2.55 +/- 0.03, P < .05). PCR analyses indicated an increase in mRNA for the 5-HT2B receptor in mesenteric arteries of DOCA-salt /"hypertensive"/ arteries, supporting an increase in receptor number. Taken together these studies demonstrate significant changes in 5-HT receptor signal transduction in DOCA-salt /"hypertension"/, both at the level of the receptor and G protein and may provide one reason why ketanserin has proved to be a relatively ineffective antihypertensive agent in some forms of /"hypertension"/. | [
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8741319 | A newly identified exonic mutation of the WT1 gene in a patient with Denys-Drash syndrome. | An 11 month old boy with hypospadias and bilateral undescended testes developed renal failure. Denys-Drash syndrome was suspected and molecular analysis of the WT1 gene was performed, although no Wilms' tumor was identified. Direct sequencing analysis of genomic DNA from this patient revealed a G to A transition resulting in 366Arg to Leu substitution in exon 8 which has hitherto not been described. This newly identified mutation will help in the understanding of functional domains and in making a diagnosis of Denys-Drash syndrome. | A newly identified exonic mutation of the /"WT1"/ gene in a patient with /"Denys-Drash syndrome"/. | An 11 month old boy with hypospadias and bilateral undescended testes developed renal failure. /"Denys-Drash syndrome"/ was suspected and molecular analysis of the /"WT1"/ gene was performed, although no Wilms' tumor was identified. Direct sequencing analysis of genomic DNA from this patient revealed a G to A transition resulting in 366Arg to Leu substitution in exon 8 which has hitherto not been described. This newly identified mutation will help in the understanding of functional domains and in making a diagnosis of /"Denys-Drash syndrome"/. | [
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8741319 | A newly identified exonic mutation of the WT1 gene in a patient with Denys-Drash syndrome. | An 11 month old boy with hypospadias and bilateral undescended testes developed renal failure. Denys-Drash syndrome was suspected and molecular analysis of the WT1 gene was performed, although no Wilms' tumor was identified. Direct sequencing analysis of genomic DNA from this patient revealed a G to A transition resulting in 366Arg to Leu substitution in exon 8 which has hitherto not been described. This newly identified mutation will help in the understanding of functional domains and in making a diagnosis of Denys-Drash syndrome. | A newly identified exonic mutation of the /"WT1"/ gene in a patient with Denys-Drash syndrome. | An 11 month old boy with /"hypospadias"/ and bilateral undescended testes developed renal failure. Denys-Drash syndrome was suspected and molecular analysis of the /"WT1"/ gene was performed, although no Wilms' tumor was identified. Direct sequencing analysis of genomic DNA from this patient revealed a G to A transition resulting in 366Arg to Leu substitution in exon 8 which has hitherto not been described. This newly identified mutation will help in the understanding of functional domains and in making a diagnosis of Denys-Drash syndrome. | [
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8757534 | A novel mutation in the ferrochelatase gene associated with erythropoietic protoporphyria. | Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by mutations of the ferrochelatase gene. We investigated a Japanese patient with a dominant form of erythropoietic protoporphyria for a ferrochelatase mutation. Sequence analysis of the proband's ferrochelatase cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in erythropoietic protoporphyria. An increase in ferrochelatase activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of ferrochelatase suggested that the Ile186-->Thr mutation changed the original beta-sheet structure to an alpha helix in the region including amino acid residue of mutation. We conclude that, in the patient, the Ile186-->Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing erythropoietic protoporphyria. | A novel mutation in the /"ferrochelatase"/ gene associated with /"erythropoietic protoporphyria"/. | /"Erythropoietic protoporphyria"/ (/"EPP"/) is a hereditary disorder caused by mutations of the /"ferrochelatase"/ gene. We investigated a Japanese patient with a dominant form of /"erythropoietic protoporphyria"/ for a /"ferrochelatase"/ mutation. Sequence analysis of the proband's /"ferrochelatase"/ cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in /"erythropoietic protoporphyria"/. An increase in /"ferrochelatase"/ activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of /"ferrochelatase"/ suggested that the Ile186-->Thr mutation changed the original beta-sheet structure to an alpha helix in the region including amino acid residue of mutation. We conclude that, in the patient, the Ile186-->Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing /"erythropoietic protoporphyria"/. | [
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} | Yes |
8757534 | A novel mutation in the ferrochelatase gene associated with erythropoietic protoporphyria. | Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by mutations of the ferrochelatase gene. We investigated a Japanese patient with a dominant form of erythropoietic protoporphyria for a ferrochelatase mutation. Sequence analysis of the proband's ferrochelatase cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in erythropoietic protoporphyria. An increase in ferrochelatase activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of ferrochelatase suggested that the Ile186-->Thr mutation changed the original beta-sheet structure to an alpha helix in the region including amino acid residue of mutation. We conclude that, in the patient, the Ile186-->Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing erythropoietic protoporphyria. | A novel mutation in the /"ferrochelatase"/ gene associated with erythropoietic protoporphyria. | Erythropoietic protoporphyria (EPP) is a /"hereditary disorder"/ caused by mutations of the /"ferrochelatase"/ gene. We investigated a Japanese patient with a dominant form of erythropoietic protoporphyria for a /"ferrochelatase"/ mutation. Sequence analysis of the proband's /"ferrochelatase"/ cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in erythropoietic protoporphyria. An increase in /"ferrochelatase"/ activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of /"ferrochelatase"/ suggested that the Ile186-->Thr mutation changed the original beta-sheet structure to an alpha helix in the region including amino acid residue of mutation. We conclude that, in the patient, the Ile186-->Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing erythropoietic protoporphyria. | [
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8822954 | Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia. | We report here two new cases of glucose phosphate isomerase (GPI) deficiency associated with hemolytic anemia and present the results of molecular analysis of the five Japanese GPI variants. A Japanese girl (GPI Fukuoka) had an episode of prolonged neonatal jaundice and at 3 years of age was admitted due to acute hemolytic crisis occurring with upper respiratory tract infection. Red blood cell (RBC) GPI activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased. A 54-year-old Japanese man (GPI Iwate) was hospitalized due to chronic active hepatitis, and compensated hemolysis was noted. RBC GPI activity of the proband was decreased to 18.8%, and the GSH content was about half of the normal mean value. Sequencing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG-->CGG (343Gln-->Arg), 14ACC-->A7C (5Thr-->lle), 671ACG-->A7G (224Thr-->Met), and 1615GAC-->AAC (539Asp-->Asn) in GPI Narita, GPI Matsumoto, GPI Iwate, and GPI Fukuoka, respectively. We also identified GPI Kinki as a compound heterozygote of 1124ACA-->AGA(375Thr-->Arg)/ 1615GAC-->AAC(539Asp-->Asn). Our findings, together with the previous results of other investigators, showed that the GPI gene mutations so far identified were heterogeneous, although most GPI variants had common biochemical characteristics such as heat instability and normal kinetics. Several amino acid substitutions were identified in the proximity of the catalytically important amino acid residues such as Ser/Asp 159/160, Asp341, and Lys518, which have been identified in the structural analysis of the pig GPI. The molecular characterization of human GPI variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as the structure-function relationship of this enzyme. | Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia. | We report here two new cases of glucose phosphate isomerase (/"GPI"/) deficiency associated with /"hemolytic anemia"/ and present the results of molecular analysis of the five Japanese /"GPI"/ variants. A Japanese girl (/"GPI"/ Fukuoka) had an episode of prolonged neonatal jaundice and at 3 years of age was admitted due to acute hemolytic crisis occurring with upper respiratory tract infection. Red blood cell (RBC) /"GPI"/ activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased. A 54-year-old Japanese man (/"GPI"/ Iwate) was hospitalized due to chronic active hepatitis, and compensated hemolysis was noted. RBC /"GPI"/ activity of the proband was decreased to 18.8%, and the GSH content was about half of the normal mean value. Sequencing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG-->CGG (343Gln-->Arg), 14ACC-->A7C (5Thr-->lle), 671ACG-->A7G (224Thr-->Met), and 1615GAC-->AAC (539Asp-->Asn) in /"GPI"/ Narita, /"GPI"/ Matsumoto, /"GPI"/ Iwate, and /"GPI"/ Fukuoka, respectively. We also identified /"GPI"/ Kinki as a compound heterozygote of 1124ACA-->AGA(375Thr-->Arg)/ 1615GAC-->AAC(539Asp-->Asn). Our findings, together with the previous results of other investigators, showed that the /"GPI"/ gene mutations so far identified were heterogeneous, although most /"GPI"/ variants had common biochemical characteristics such as heat instability and normal kinetics. Several amino acid substitutions were identified in the proximity of the catalytically important amino acid residues such as Ser/Asp 159/160, Asp341, and Lys518, which have been identified in the structural analysis of the pig /"GPI"/. The molecular characterization of human /"GPI"/ variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as the structure-function relationship of this enzyme. | [
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8822954 | Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia. | We report here two new cases of glucose phosphate isomerase (GPI) deficiency associated with hemolytic anemia and present the results of molecular analysis of the five Japanese GPI variants. A Japanese girl (GPI Fukuoka) had an episode of prolonged neonatal jaundice and at 3 years of age was admitted due to acute hemolytic crisis occurring with upper respiratory tract infection. Red blood cell (RBC) GPI activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased. A 54-year-old Japanese man (GPI Iwate) was hospitalized due to chronic active hepatitis, and compensated hemolysis was noted. RBC GPI activity of the proband was decreased to 18.8%, and the GSH content was about half of the normal mean value. Sequencing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG-->CGG (343Gln-->Arg), 14ACC-->A7C (5Thr-->lle), 671ACG-->A7G (224Thr-->Met), and 1615GAC-->AAC (539Asp-->Asn) in GPI Narita, GPI Matsumoto, GPI Iwate, and GPI Fukuoka, respectively. We also identified GPI Kinki as a compound heterozygote of 1124ACA-->AGA(375Thr-->Arg)/ 1615GAC-->AAC(539Asp-->Asn). Our findings, together with the previous results of other investigators, showed that the GPI gene mutations so far identified were heterogeneous, although most GPI variants had common biochemical characteristics such as heat instability and normal kinetics. Several amino acid substitutions were identified in the proximity of the catalytically important amino acid residues such as Ser/Asp 159/160, Asp341, and Lys518, which have been identified in the structural analysis of the pig GPI. The molecular characterization of human GPI variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as the structure-function relationship of this enzyme. | Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia. | We report here two new cases of glucose phosphate isomerase (/"GPI"/) deficiency associated with hemolytic anemia and present the results of molecular analysis of the five Japanese /"GPI"/ variants. A Japanese girl (/"GPI"/ Fukuoka) had an episode of prolonged neonatal jaundice and at 3 years of age was admitted due to acute /"hemolytic crisis"/ occurring with upper respiratory tract infection. Red blood cell (RBC) /"GPI"/ activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased. A 54-year-old Japanese man (/"GPI"/ Iwate) was hospitalized due to chronic active hepatitis, and compensated /"hemolysis"/ was noted. RBC /"GPI"/ activity of the proband was decreased to 18.8%, and the GSH content was about half of the normal mean value. Sequencing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG-->CGG (343Gln-->Arg), 14ACC-->A7C (5Thr-->lle), 671ACG-->A7G (224Thr-->Met), and 1615GAC-->AAC (539Asp-->Asn) in /"GPI"/ Narita, /"GPI"/ Matsumoto, /"GPI"/ Iwate, and /"GPI"/ Fukuoka, respectively. We also identified /"GPI"/ Kinki as a compound heterozygote of 1124ACA-->AGA(375Thr-->Arg)/ 1615GAC-->AAC(539Asp-->Asn). Our findings, together with the previous results of other investigators, showed that the /"GPI"/ gene mutations so far identified were heterogeneous, although most /"GPI"/ variants had common biochemical characteristics such as heat instability and normal kinetics. Several amino acid substitutions were identified in the proximity of the catalytically important amino acid residues such as Ser/Asp 159/160, Asp341, and Lys518, which have been identified in the structural analysis of the pig /"GPI"/. The molecular characterization of human /"GPI"/ variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as the structure-function relationship of this enzyme. | [
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8834250 | Acid alpha-glucosidase deficiency: identification and expression of a missense mutation (S529V) in a Japanese adult phenotype. | We report a missense mutation in an adult Japanese patient with acid alpha-glucosidase (GAA) deficiency. A TC to GT transition at nucleotides 1585-1586, was identified. This transition resulted in an amino acid substitution of Ser-529 to Val (S529V) in exon 11. We also have demonstrated that the S529V mutation abolishes the catalytic activity of the enzyme. Our data suggest that this mutation is the cause of the clinical manifestation known as adult-onset GAA deficiency. The missense mutation described here is a new mutation, and the first identified in Japanese patients with GAA deficiency. | Acid /"alpha-glucosidase deficiency"/: identification and expression of a missense mutation (S529V) in a Japanese adult phenotype. | We report a missense mutation in an adult Japanese patient with acid alpha-glucosidase (/"GAA"/) deficiency. A TC to GT transition at nucleotides 1585-1586, was identified. This transition resulted in an amino acid substitution of Ser-529 to Val (S529V) in exon 11. We also have demonstrated that the S529V mutation abolishes the catalytic activity of the enzyme. Our data suggest that this mutation is the cause of the clinical manifestation known as adult-onset /"GAA deficiency"/. The missense mutation described here is a new mutation, and the first identified in Japanese patients with /"GAA deficiency"/. | [
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} | Yes |
8837968 | An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia. | Since abnormalities of brain development play a role in the aetiology of schizophrenia, growth factors, known to play a role in neurodevelopment, such as neurotrophin-3 (NT-3), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the NT-3 gene has been reported as occurring more frequently in a sample of Japanese schizophrenics compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian schizophrenic patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and, in a test of allalleles, the patients and controls did not differ significantly in allele frequencies. However, the male schizophrenics were more likely than male controls to have the A3/147 bp allele (P = 0.029). | An association study of a /"neurotrophin-3"/ (/"NT-3"/) gene polymorphism with /"schizophrenia"/. | Since abnormalities of brain development play a role in the aetiology of /"schizophrenia"/, growth factors, known to play a role in neurodevelopment, such as /"neurotrophin-3"/ (/"NT-3"/), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the /"NT-3"/ gene has been reported as occurring more frequently in a sample of Japanese /"schizophrenics"/ compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian /"schizophrenic"/ patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and, in a test of allalleles, the patients and controls did not differ significantly in allele frequencies. However, the male /"schizophrenics"/ were more likely than male controls to have the A3/147 bp allele (P = 0.029). | [
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"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenics"
},
{
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"end_idx": "40",
"entity_id": "4908",
"entity_type": "Gene",
"text_name": "neurotrophin-3"
},
{
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"end_idx": "46",
"entity_id": "4908",
"entity_type": "Gene",
"text_name": "NT-3"
},
{
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},
{
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"entity_id": "4908",
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},
{
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"entity_id": "4908",
"entity_type": "Gene",
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}
] | {
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"entity_id": "4908",
"entity_type": "Gene",
"text_name": "neurotrophin-3"
} | {
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"end_idx": "496",
"entity_id": "D012559",
"entity_type": "Disease",
"text_name": "schizophrenics"
} | Yes |
8837968 | An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia. | Since abnormalities of brain development play a role in the aetiology of schizophrenia, growth factors, known to play a role in neurodevelopment, such as neurotrophin-3 (NT-3), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the NT-3 gene has been reported as occurring more frequently in a sample of Japanese schizophrenics compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian schizophrenic patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and, in a test of allalleles, the patients and controls did not differ significantly in allele frequencies. However, the male schizophrenics were more likely than male controls to have the A3/147 bp allele (P = 0.029). | An association study of a /"neurotrophin-3"/ (/"NT-3"/) gene polymorphism with schizophrenia. | Since /"abnormalities of brain"/ development play a role in the aetiology of schizophrenia, growth factors, known to play a role in neurodevelopment, such as /"neurotrophin-3"/ (/"NT-3"/), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the /"NT-3"/ gene has been reported as occurring more frequently in a sample of Japanese schizophrenics compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian schizophrenic patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and, in a test of allalleles, the patients and controls did not differ significantly in allele frequencies. However, the male schizophrenics were more likely than male controls to have the A3/147 bp allele (P = 0.029). | [
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] | {
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"text_name": "neurotrophin-3"
} | {
"begin_idx": "92",
"end_idx": "114",
"entity_id": "D001927",
"entity_type": "Disease",
"text_name": "abnormalities of brain"
} | No |
8884076 | Ehlers-Danlos syndrome type IV caused by Gly400Glu, Gly595Cys and Gly1003Asp substitutions in collagen III: clinical features, biochemical screening, and molecular confirmation. | Three patients with Ehlers-Danlos syndrome type IV (EDS IV) and biochemical evidence of structural defects in collagen III were investigated for mutations within the collagen III gene (COL3A1). Single strand conformation polymorphism analysis of alpha 1 (III) cDNA indicated the presence of different heterozygous sequence changes in each of the patients. Nucleotide sequencing revealed mutations leading to the substitution of glycine 400 with glutamic acid, glycine 595 with cysteine, and glycine 1003 with aspartic acid. EDS IV is a life-threatening disorder which, as the clinical histories of our patients and their families show, still often escapes diagnosis. Biochemical and molecular studies can clarify the diagnosis and help provide appropriate management and counselling. | /"Ehlers-Danlos syndrome type IV"/ caused by Gly400Glu, Gly595Cys and Gly1003Asp substitutions in collagen III: clinical features, biochemical screening, and molecular confirmation. | Three patients with /"Ehlers-Danlos syndrome type IV"/ (/"EDS IV"/) and biochemical evidence of structural defects in collagen III were investigated for mutations within the collagen III gene (/"COL3A1"/). Single strand conformation polymorphism analysis of alpha 1 (III) cDNA indicated the presence of different heterozygous sequence changes in each of the patients. Nucleotide sequencing revealed mutations leading to the substitution of glycine 400 with glutamic acid, glycine 595 with cysteine, and glycine 1003 with aspartic acid. /"EDS IV"/ is a life-threatening disorder which, as the clinical histories of our patients and their families show, still often escapes diagnosis. Biochemical and molecular studies can clarify the diagnosis and help provide appropriate management and counselling. | [
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"text_name": "COL3A1"
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"entity_id": "D004535",
"entity_type": "Disease",
"text_name": "Ehlers-Danlos syndrome type IV"
} | Yes |
8909447 | Mutation of the prion protein gene at codon 208 in familial Creutzfeldt-Jakob disease. | Four point mutations and one insertion within the prion protein (PrP) gene have been tightly linked to the development of inherited prion disease. We developed a denaturing gradient gel electrophoresis system that allowed us to screen the entire open reading frame of the PrP gene. Using this system, we found a new mutation of the PrP gene in a patient with pathologically confirmed Creutzfeldt-Jakob disease and a negative family history for dementia. DNA sequencing revealed an adenine substitution for guanine at the second position of codon 208, which results in the nonconservative substitution of histidine for arginine. The same PrP mutation was identified in another younger member of the pedigree but was not present in more than 200 alleles tested. Such findings suggest that the frequency of inherited prion disease might be higher than ascertained by clinical history alone. | Mutation of the /"prion protein"/ gene at codon 208 in /"familial Creutzfeldt-Jakob disease"/. | Four point mutations and one insertion within the /"prion protein"/ (/"PrP"/) gene have been tightly linked to the development of inherited prion disease. We developed a denaturing gradient gel electrophoresis system that allowed us to screen the entire open reading frame of the /"PrP"/ gene. Using this system, we found a new mutation of the /"PrP"/ gene in a patient with pathologically confirmed /"Creutzfeldt-Jakob disease"/ and a negative family history for dementia. DNA sequencing revealed an adenine substitution for guanine at the second position of codon 208, which results in the nonconservative substitution of histidine for arginine. The same /"PrP"/ mutation was identified in another younger member of the pedigree but was not present in more than 200 alleles tested. Such findings suggest that the frequency of inherited prion disease might be higher than ascertained by clinical history alone. | [
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"text_name": "dementia"
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] | {
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} | {
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"entity_id": "D007562",
"entity_type": "Disease",
"text_name": "familial Creutzfeldt-Jakob disease"
} | Yes |
8909447 | Mutation of the prion protein gene at codon 208 in familial Creutzfeldt-Jakob disease. | Four point mutations and one insertion within the prion protein (PrP) gene have been tightly linked to the development of inherited prion disease. We developed a denaturing gradient gel electrophoresis system that allowed us to screen the entire open reading frame of the PrP gene. Using this system, we found a new mutation of the PrP gene in a patient with pathologically confirmed Creutzfeldt-Jakob disease and a negative family history for dementia. DNA sequencing revealed an adenine substitution for guanine at the second position of codon 208, which results in the nonconservative substitution of histidine for arginine. The same PrP mutation was identified in another younger member of the pedigree but was not present in more than 200 alleles tested. Such findings suggest that the frequency of inherited prion disease might be higher than ascertained by clinical history alone. | Mutation of the /"prion protein"/ gene at codon 208 in familial Creutzfeldt-Jakob disease. | Four point mutations and one insertion within the /"prion protein"/ (/"PrP"/) gene have been tightly linked to the development of inherited prion disease. We developed a denaturing gradient gel electrophoresis system that allowed us to screen the entire open reading frame of the /"PrP"/ gene. Using this system, we found a new mutation of the /"PrP"/ gene in a patient with pathologically confirmed Creutzfeldt-Jakob disease and a negative family history for /"dementia"/. DNA sequencing revealed an adenine substitution for guanine at the second position of codon 208, which results in the nonconservative substitution of histidine for arginine. The same /"PrP"/ mutation was identified in another younger member of the pedigree but was not present in more than 200 alleles tested. Such findings suggest that the frequency of inherited prion disease might be higher than ascertained by clinical history alone. | [
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"text_name": "prion protein"
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}
] | {
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"entity_id": "5621",
"entity_type": "Gene",
"text_name": "PrP"
} | {
"begin_idx": "531",
"end_idx": "539",
"entity_id": "D003704",
"entity_type": "Disease",
"text_name": "dementia"
} | No |
8930979 | Association between a PS-1 intronic polymorphism and late onset Alzheimer's disease. | Previous work suggests an association between allele 1 and the 1-1 genotype of an intronic polymorphism in the presenilin-1 (PS-1) gene and late onset Alzheimer's disease. We found an excess of the 1-1 genotype in our late onset clinical sample (p = 0.006, one-tailed) but not in our postmortem confirmed sample, which instead exhibited an excess of allele 1 (p = 0.02, one-tailed). No interaction between PS-1 and ApoE genotype was detected and the findings remained significant when the effects of ApoE were taken into account (p = 0.03, one-tailed). These results suggest that the PS-1 polymorphism, or a locus in linkage disequilibrium with it, acts as a risk factor for late onset AD. | Association between a /"PS-1"/ intronic polymorphism and late onset /"Alzheimer's disease"/. | Previous work suggests an association between allele 1 and the 1-1 genotype of an intronic polymorphism in the /"presenilin-1"/ (/"PS-1"/) gene and late onset /"Alzheimer's disease"/. We found an excess of the 1-1 genotype in our late onset clinical sample (p = 0.006, one-tailed) but not in our postmortem confirmed sample, which instead exhibited an excess of allele 1 (p = 0.02, one-tailed). No interaction between /"PS-1"/ and ApoE genotype was detected and the findings remained significant when the effects of ApoE were taken into account (p = 0.03, one-tailed). These results suggest that the /"PS-1"/ polymorphism, or a locus in linkage disequilibrium with it, acts as a risk factor for late onset /"AD"/. | [
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"entity_type": "Disease",
"text_name": "Alzheimer's disease"
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"text_name": "presenilin-1"
},
{
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"entity_id": "5663",
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"text_name": "PS-1"
},
{
"begin_idx": "491",
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"entity_id": "5663",
"entity_type": "Gene",
"text_name": "PS-1"
},
{
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"entity_id": "5663",
"entity_type": "Gene",
"text_name": "PS-1"
}
] | {
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"end_idx": "208",
"entity_id": "5663",
"entity_type": "Gene",
"text_name": "presenilin-1"
} | {
"begin_idx": "64",
"end_idx": "83",
"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
} | Yes |
8930979 | Association between a PS-1 intronic polymorphism and late onset Alzheimer's disease. | Previous work suggests an association between allele 1 and the 1-1 genotype of an intronic polymorphism in the presenilin-1 (PS-1) gene and late onset Alzheimer's disease. We found an excess of the 1-1 genotype in our late onset clinical sample (p = 0.006, one-tailed) but not in our postmortem confirmed sample, which instead exhibited an excess of allele 1 (p = 0.02, one-tailed). No interaction between PS-1 and ApoE genotype was detected and the findings remained significant when the effects of ApoE were taken into account (p = 0.03, one-tailed). These results suggest that the PS-1 polymorphism, or a locus in linkage disequilibrium with it, acts as a risk factor for late onset AD. | Association between a PS-1 intronic polymorphism and late onset /"Alzheimer's disease"/. | Previous work suggests an association between allele 1 and the 1-1 genotype of an intronic polymorphism in the presenilin-1 (PS-1) gene and late onset /"Alzheimer's disease"/. We found an excess of the 1-1 genotype in our late onset clinical sample (p = 0.006, one-tailed) but not in our postmortem confirmed sample, which instead exhibited an excess of allele 1 (p = 0.02, one-tailed). No interaction between PS-1 and /"ApoE"/ genotype was detected and the findings remained significant when the effects of /"ApoE"/ were taken into account (p = 0.03, one-tailed). These results suggest that the PS-1 polymorphism, or a locus in linkage disequilibrium with it, acts as a risk factor for late onset /"AD"/. | [
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"entity_type": "Disease",
"text_name": "Alzheimer's disease"
},
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},
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},
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},
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},
{
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}
] | {
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"text_name": "ApoE"
} | {
"begin_idx": "64",
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"entity_id": "D000544",
"entity_type": "Disease",
"text_name": "Alzheimer's disease"
} | No |
8942447 | Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia. | OBJECTIVE: The authors investigated the human leukocyte antigen (HLA) DRB1*04 gene in schizophrenic patients because it is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with schizophrenia. The HLA DQB1*0602 allele was also studied because of previous reports of genetic association between it and schizophrenia. Maternal HLA was investigated because of the reported association between prenatal influenza and schizophrenia and the central role of HLA molecules in the immune response to viral infections. METHOD: Polymerase chain reactions and sequence-specific oligonucleotide probes were used to genotype 94 unrelated patients with DSM-III-R schizophrenia, 92 mothers of schizophrenic offspring who were not related either to each other or to the 94 patients, and 177 healthy comparison subjects. RESULTS: The frequency of DRB1*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. No significant differences were found for DQB1*0602. CONCLUSIONS: DRB1*04 alleles may partially account for the genetic predisposition to schizophrenia. The association reported here may be explained by genetic linkage or by an autoimmune pathophysiology for a proportion of schizophrenia cases. Alternatively, it may be that maternal B lymphocytes that do not express the DR4 antigen encoded by DRB1*04 respond to influenza virus by producing antibodies that perturb neurodevelopment, thus underpinning a proportion of schizophrenia cases. | Genetic association of the /"HLA DRB1"/ gene locus on chromosome 6p21.3 with /"schizophrenia"/. | OBJECTIVE: The authors investigated the human /"leukocyte antigen (HLA) DRB1"/*04 gene in /"schizophrenic"/ patients because it is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with /"schizophrenia"/. The HLA DQB1*0602 allele was also studied because of previous reports of genetic association between it and /"schizophrenia"/. Maternal HLA was investigated because of the reported association between prenatal influenza and /"schizophrenia"/ and the central role of HLA molecules in the immune response to viral infections. METHOD: Polymerase chain reactions and sequence-specific oligonucleotide probes were used to genotype 94 unrelated patients with DSM-III-R /"schizophrenia"/, 92 mothers of /"schizophrenic"/ offspring who were not related either to each other or to the 94 patients, and 177 healthy comparison subjects. RESULTS: The frequency of /"DRB1"/*04 alleles was significantly lower in both the /"schizophrenic"/ patients and the unrelated mothers of /"schizophrenic"/ offspring than in the healthy comparison subjects. No significant differences were found for DQB1*0602. CONCLUSIONS: /"DRB1"/*04 alleles may partially account for the genetic predisposition to /"schizophrenia"/. The association reported here may be explained by genetic linkage or by an autoimmune pathophysiology for a proportion of /"schizophrenia"/ cases. Alternatively, it may be that maternal B lymphocytes that do not express the DR4 antigen encoded by /"DRB1"/*04 respond to influenza virus by producing antibodies that perturb neurodevelopment, thus underpinning a proportion of /"schizophrenia"/ cases. | [
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},
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},
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},
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8942447 | Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia. | OBJECTIVE: The authors investigated the human leukocyte antigen (HLA) DRB1*04 gene in schizophrenic patients because it is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with schizophrenia. The HLA DQB1*0602 allele was also studied because of previous reports of genetic association between it and schizophrenia. Maternal HLA was investigated because of the reported association between prenatal influenza and schizophrenia and the central role of HLA molecules in the immune response to viral infections. METHOD: Polymerase chain reactions and sequence-specific oligonucleotide probes were used to genotype 94 unrelated patients with DSM-III-R schizophrenia, 92 mothers of schizophrenic offspring who were not related either to each other or to the 94 patients, and 177 healthy comparison subjects. RESULTS: The frequency of DRB1*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. No significant differences were found for DQB1*0602. CONCLUSIONS: DRB1*04 alleles may partially account for the genetic predisposition to schizophrenia. The association reported here may be explained by genetic linkage or by an autoimmune pathophysiology for a proportion of schizophrenia cases. Alternatively, it may be that maternal B lymphocytes that do not express the DR4 antigen encoded by DRB1*04 respond to influenza virus by producing antibodies that perturb neurodevelopment, thus underpinning a proportion of schizophrenia cases. | Genetic association of the /"HLA DRB1"/ gene locus on chromosome 6p21.3 with schizophrenia. | OBJECTIVE: The authors investigated the human /"leukocyte antigen (HLA) DRB1"/*04 gene in schizophrenic patients because it is positively associated with rheumatoid arthritis, an /"autoimmune disease"/ that exhibits a strong negative association with schizophrenia. The HLA DQB1*0602 allele was also studied because of previous reports of genetic association between it and schizophrenia. Maternal HLA was investigated because of the reported association between prenatal influenza and schizophrenia and the central role of HLA molecules in the immune response to viral infections. METHOD: Polymerase chain reactions and sequence-specific oligonucleotide probes were used to genotype 94 unrelated patients with DSM-III-R schizophrenia, 92 mothers of schizophrenic offspring who were not related either to each other or to the 94 patients, and 177 healthy comparison subjects. RESULTS: The frequency of /"DRB1"/*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. No significant differences were found for DQB1*0602. CONCLUSIONS: /"DRB1"/*04 alleles may partially account for the genetic predisposition to schizophrenia. The association reported here may be explained by genetic linkage or by an autoimmune pathophysiology for a proportion of schizophrenia cases. Alternatively, it may be that maternal B lymphocytes that do not express the DR4 antigen encoded by /"DRB1"/*04 respond to influenza virus by producing antibodies that perturb neurodevelopment, thus underpinning a proportion of schizophrenia cases. | [
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} | No |
9042911 | Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. | Uridine monophosphate (UMP) synthase is a bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC). Loss of either enzymatic activity results in hereditary orotic aciduria, a rare autosomal recessive disorder characterized by retarded growth, anemia, and excessive urinary excretion of orotic acid. We have isolated the UMP synthase chromosomal gene from a lambdaEMBL-3 human genomic library and report a single-copy gene spanning approximately 15 kb. The UMP synthase genomic structure encodes six exons ranging in size from 115 bp to 672 bp, and all splicing junctions adhere to the canonical GT/AG rule. Cognate promoter elements implicated in glucocorticoid- and cAMP-mediated regulation as well as in liver-, myeloid-, and lymphocyte-specific expression are located within the 5' flanking sequence. Molecular investigation of UMP synthase deficiency in a Japanese orotic aciduria patient revealed mutations R96G (A-to-G transition; nt 286) and G429R (G-to-C transversion; nt 1285) in one allele and V109G (T-to-G transversion; nt 326) in the other allele. Expression of human UMP synthase cDNAs containing these mutations in pyrimidine auxotrophic Escherichia coli and in recombinant baculovirus-infected Sf21 cells demonstrates impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo. We further establish the identity of two polymorphisms, G213A (v = .26) and 440Gpoly (v = .27) located in exons 3 and 6, respectively, which did not significantly compromise either OPRT or ODC function. | Molecular cloning of the human /"UMP synthase"/ gene and characterization of point mutations in two hereditary orotic aciduria families. | /"Uridine monophosphate (UMP) synthase"/ is a bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, /"orotate phosphoribosyltransferase"/ (/"OPRT"/) and orotidine-5'-monophosphate decarboxylase (ODC). Loss of either enzymatic activity results in hereditary orotic aciduria, a rare autosomal recessive disorder characterized by retarded growth, anemia, and excessive urinary excretion of orotic acid. We have isolated the /"UMP synthase"/ chromosomal gene from a lambdaEMBL-3 human genomic library and report a single-copy gene spanning approximately 15 kb. The /"UMP synthase"/ genomic structure encodes six exons ranging in size from 115 bp to 672 bp, and all splicing junctions adhere to the canonical GT/AG rule. Cognate promoter elements implicated in glucocorticoid- and cAMP-mediated regulation as well as in liver-, myeloid-, and lymphocyte-specific expression are located within the 5' flanking sequence. Molecular investigation of /"UMP synthase deficiency"/ in a Japanese /"orotic aciduria"/ patient revealed mutations R96G (A-to-G transition; nt 286) and G429R (G-to-C transversion; nt 1285) in one allele and V109G (T-to-G transversion; nt 326) in the other allele. Expression of human /"UMP synthase"/ cDNAs containing these mutations in pyrimidine auxotrophic Escherichia coli and in recombinant baculovirus-infected Sf21 cells demonstrates impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo. We further establish the identity of two polymorphisms, G213A (v = .26) and 440Gpoly (v = .27) located in exons 3 and 6, respectively, which did not significantly compromise either /"OPRT"/ or ODC function. | [
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9042911 | Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. | Uridine monophosphate (UMP) synthase is a bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC). Loss of either enzymatic activity results in hereditary orotic aciduria, a rare autosomal recessive disorder characterized by retarded growth, anemia, and excessive urinary excretion of orotic acid. We have isolated the UMP synthase chromosomal gene from a lambdaEMBL-3 human genomic library and report a single-copy gene spanning approximately 15 kb. The UMP synthase genomic structure encodes six exons ranging in size from 115 bp to 672 bp, and all splicing junctions adhere to the canonical GT/AG rule. Cognate promoter elements implicated in glucocorticoid- and cAMP-mediated regulation as well as in liver-, myeloid-, and lymphocyte-specific expression are located within the 5' flanking sequence. Molecular investigation of UMP synthase deficiency in a Japanese orotic aciduria patient revealed mutations R96G (A-to-G transition; nt 286) and G429R (G-to-C transversion; nt 1285) in one allele and V109G (T-to-G transversion; nt 326) in the other allele. Expression of human UMP synthase cDNAs containing these mutations in pyrimidine auxotrophic Escherichia coli and in recombinant baculovirus-infected Sf21 cells demonstrates impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo. We further establish the identity of two polymorphisms, G213A (v = .26) and 440Gpoly (v = .27) located in exons 3 and 6, respectively, which did not significantly compromise either OPRT or ODC function. | Molecular cloning of the human /"UMP synthase"/ gene and characterization of point mutations in two hereditary orotic aciduria families. | /"Uridine monophosphate (UMP) synthase"/ is a bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, /"orotate phosphoribosyltransferase"/ (/"OPRT"/) and orotidine-5'-monophosphate decarboxylase (ODC). Loss of either enzymatic activity results in hereditary orotic aciduria, a rare autosomal recessive disorder characterized by retarded growth, /"anemia"/, and excessive urinary excretion of orotic acid. We have isolated the /"UMP synthase"/ chromosomal gene from a lambdaEMBL-3 human genomic library and report a single-copy gene spanning approximately 15 kb. The /"UMP synthase"/ genomic structure encodes six exons ranging in size from 115 bp to 672 bp, and all splicing junctions adhere to the canonical GT/AG rule. Cognate promoter elements implicated in glucocorticoid- and cAMP-mediated regulation as well as in liver-, myeloid-, and lymphocyte-specific expression are located within the 5' flanking sequence. Molecular investigation of UMP synthase deficiency in a Japanese orotic aciduria patient revealed mutations R96G (A-to-G transition; nt 286) and G429R (G-to-C transversion; nt 1285) in one allele and V109G (T-to-G transversion; nt 326) in the other allele. Expression of human /"UMP synthase"/ cDNAs containing these mutations in pyrimidine auxotrophic Escherichia coli and in recombinant baculovirus-infected Sf21 cells demonstrates impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo. We further establish the identity of two polymorphisms, G213A (v = .26) and 440Gpoly (v = .27) located in exons 3 and 6, respectively, which did not significantly compromise either /"OPRT"/ or ODC function. | [
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9047388 | Alterations of the p16 gene in head and neck cancer: frequency and association with p53, PRAD-1 and HPV. | Alterations, especially homozygous deletions, of the putative tumor suppressor gene, p16 (p16INK4A, MTS1, CDKN2) have been found in tumor cell lines from a variety of neoplasms. Recent studies have reported frequent p16 gene deletions in cell lines from squamous cell carcinomas of the head and neck (SCCHN), although the prevalence of alterations was variable in primary tumors. This study determined the prevalence of point mutations and deletions of the p16 gene in 33 SCCHN. In addition, the association of p16 gene alterations and abnormalities of p53, PRAD-1 (cyclin D1), and the presence of human papillomavirus (HPV) was examined. We found an overall prevalence of p16 alterations of 36% (nine deletions, three single base substitutions, including one polymorphism). Seven tumors (of 29, 24%) had an alteration of p16 and p53; five (of 33, 15%) had alterations of p16 and PRAD-1; three (of 29, 10%) had alterations of all three genes. In addition, of the five tumors with human papillomavirus detected, only one also had a p16 gene alteration. The results indicate a potentially important role for the p16 gene in head and neck tumorigenesis. In addition, the presence of tumors with multiple somatic gene alterations suggest a possible interaction in the dysregulation of the cell cycle. | Alterations of the /"p16"/ gene in /"head and neck cancer"/: frequency and association with p53, PRAD-1 and HPV. | Alterations, especially homozygous deletions, of the putative tumor suppressor gene, /"p16"/ (/"p16INK4A"/, /"MTS1"/, /"CDKN2"/) have been found in tumor cell lines from a variety of neoplasms. Recent studies have reported frequent /"p16"/ gene deletions in cell lines from squamous cell carcinomas of the head and neck (SCCHN), although the prevalence of alterations was variable in primary tumors. This study determined the prevalence of point mutations and deletions of the /"p16"/ gene in 33 SCCHN. In addition, the association of /"p16"/ gene alterations and abnormalities of p53, PRAD-1 (cyclin D1), and the presence of human papillomavirus (HPV) was examined. We found an overall prevalence of /"p16"/ alterations of 36% (nine deletions, three single base substitutions, including one polymorphism). Seven tumors (of 29, 24%) had an alteration of /"p16"/ and p53; five (of 33, 15%) had alterations of /"p16"/ and PRAD-1; three (of 29, 10%) had alterations of all three genes. In addition, of the five tumors with human papillomavirus detected, only one also had a /"p16"/ gene alteration. The results indicate a potentially important role for the /"p16"/ gene in head and neck tumorigenesis. In addition, the presence of tumors with multiple somatic gene alterations suggest a possible interaction in the dysregulation of the cell cycle. | [
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9047388 | Alterations of the p16 gene in head and neck cancer: frequency and association with p53, PRAD-1 and HPV. | Alterations, especially homozygous deletions, of the putative tumor suppressor gene, p16 (p16INK4A, MTS1, CDKN2) have been found in tumor cell lines from a variety of neoplasms. Recent studies have reported frequent p16 gene deletions in cell lines from squamous cell carcinomas of the head and neck (SCCHN), although the prevalence of alterations was variable in primary tumors. This study determined the prevalence of point mutations and deletions of the p16 gene in 33 SCCHN. In addition, the association of p16 gene alterations and abnormalities of p53, PRAD-1 (cyclin D1), and the presence of human papillomavirus (HPV) was examined. We found an overall prevalence of p16 alterations of 36% (nine deletions, three single base substitutions, including one polymorphism). Seven tumors (of 29, 24%) had an alteration of p16 and p53; five (of 33, 15%) had alterations of p16 and PRAD-1; three (of 29, 10%) had alterations of all three genes. In addition, of the five tumors with human papillomavirus detected, only one also had a p16 gene alteration. The results indicate a potentially important role for the p16 gene in head and neck tumorigenesis. In addition, the presence of tumors with multiple somatic gene alterations suggest a possible interaction in the dysregulation of the cell cycle. | Alterations of the /"p16"/ gene in head and neck cancer: frequency and association with p53, PRAD-1 and HPV. | Alterations, especially homozygous deletions, of the putative tumor suppressor gene, /"p16"/ (/"p16INK4A"/, /"MTS1"/, /"CDKN2"/) have been found in tumor cell lines from a variety of neoplasms. Recent studies have reported frequent /"p16"/ gene deletions in cell lines from /"squamous cell carcinomas of the head and neck"/ (/"SCCHN"/), although the prevalence of alterations was variable in primary tumors. This study determined the prevalence of point mutations and deletions of the /"p16"/ gene in 33 /"SCCHN"/. In addition, the association of /"p16"/ gene alterations and abnormalities of p53, PRAD-1 (cyclin D1), and the presence of human papillomavirus (HPV) was examined. We found an overall prevalence of /"p16"/ alterations of 36% (nine deletions, three single base substitutions, including one polymorphism). Seven tumors (of 29, 24%) had an alteration of /"p16"/ and p53; five (of 33, 15%) had alterations of /"p16"/ and PRAD-1; three (of 29, 10%) had alterations of all three genes. In addition, of the five tumors with human papillomavirus detected, only one also had a /"p16"/ gene alteration. The results indicate a potentially important role for the /"p16"/ gene in head and neck tumorigenesis. In addition, the presence of tumors with multiple somatic gene alterations suggest a possible interaction in the dysregulation of the cell cycle. | [
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9070496 | Doxorubicin sensitizes human bladder carcinoma cells to Fas-mediated cytotoxicity. | BACKGROUND: The resistance of bladder carcinoma to anticancer chemotherapeutic agents remains a major problem. Hence, several immunotherapeutic approaches have been developed to treat the drug-resistant cancer cells. Fas antigen (Fas) and Fas ligand participate in cytotoxicity mediated by T lymphocytes and natural killer cells. Like Fas ligand, anti-Fas monoclonal antibody (MoAb) induces apoptosis of the cells expressing Fas. This study examined whether bladder carcinoma cells are sensitive to cytotoxicity mediated by anti-Fas MoAb and whether anticancer agents synergize with anti-Fas MoAb in cytotoxicity. METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. RESULTS: The T24 human bladder carcinoma cell line constitutively expressed the Fas on the cell surface; however, T24 line was resistant to anti-Fas MoAb. Treatment of T24 cells with anti-Fas MoAb in combination with mitomycin C, methotrexate, or 5-fluorouracil did not overcome their resistance to these agents. However, treatment of T24 cells with a combination of anti-Fas MoAb and doxorubicin resulted in a synergistic cytotoxic effect. In addition, the doxorubicin-resistant T24 cells were sensitive to treatment with a combination of anti-Fas MoAb and doxorubicin. Synergy was also achieved in three other bladder carcinoma cell lines and four freshly derived human bladder carcinoma cells. Treatment with anti-Fas MoAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on T24 cells. The mechanisms of synergy were examined. Anti-Fas MoAb did not affect the intracellular accumulation of doxorubicin, the expression of P-glycoprotein, or the expression of the antioxidant glutathione S-transferase-pi mRNA. However, treatment with doxorubicin enhanced the expression of Fas on T24 cells. CONCLUSIONS: This study demonstrated that treatment of bladder carcinoma cells with doxorubicin sensitized the cells to lysis by anti-Fas MoAb. The synergistic effect obtained with established doxorubicin-resistant bladder carcinoma cells and freshly isolated bladder carcinoma cells suggests that drug-resistant bladder carcinoma cells can be sensitized by doxorubicin to Fas- and Fas ligant-mediated cytotoxicity by lymphocytes. Furthermore, the sensitization required low concentrations of doxorubicin, thus supporting the in vivo application of a combination of chemotherapy and immunotherapy in the treatment of drug-resistant and/or immunotherapy-resistant bladder carcinoma. | Doxorubicin sensitizes human /"bladder carcinoma"/ cells to Fas-mediated cytotoxicity. | BACKGROUND: The resistance of /"bladder carcinoma"/ to anticancer chemotherapeutic agents remains a major problem. Hence, several immunotherapeutic approaches have been developed to treat the drug-resistant cancer cells. /"Fas antigen"/ (Fas) and Fas ligand participate in cytotoxicity mediated by T lymphocytes and natural killer cells. Like Fas ligand, anti-Fas monoclonal antibody (MoAb) induces apoptosis of the cells expressing Fas. This study examined whether /"bladder carcinoma"/ cells are sensitive to cytotoxicity mediated by anti-Fas MoAb and whether anticancer agents synergize with anti-Fas MoAb in cytotoxicity. METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. RESULTS: The T24 human /"bladder carcinoma"/ cell line constitutively expressed the Fas on the cell surface; however, T24 line was resistant to anti-Fas MoAb. Treatment of T24 cells with anti-Fas MoAb in combination with mitomycin C, methotrexate, or 5-fluorouracil did not overcome their resistance to these agents. However, treatment of T24 cells with a combination of anti-Fas MoAb and doxorubicin resulted in a synergistic cytotoxic effect. In addition, the doxorubicin-resistant T24 cells were sensitive to treatment with a combination of anti-Fas MoAb and doxorubicin. Synergy was also achieved in three other /"bladder carcinoma"/ cell lines and four freshly derived human /"bladder carcinoma"/ cells. Treatment with anti-Fas MoAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on T24 cells. The mechanisms of synergy were examined. Anti-Fas MoAb did not affect the intracellular accumulation of doxorubicin, the expression of P-glycoprotein, or the expression of the antioxidant glutathione S-transferase-pi mRNA. However, treatment with doxorubicin enhanced the expression of Fas on T24 cells. CONCLUSIONS: This study demonstrated that treatment of /"bladder carcinoma"/ cells with doxorubicin sensitized the cells to lysis by anti-Fas MoAb. The synergistic effect obtained with established doxorubicin-resistant /"bladder carcinoma"/ cells and freshly isolated /"bladder carcinoma"/ cells suggests that drug-resistant /"bladder carcinoma"/ cells can be sensitized by doxorubicin to Fas- and Fas ligant-mediated cytotoxicity by lymphocytes. Furthermore, the sensitization required low concentrations of doxorubicin, thus supporting the in vivo application of a combination of chemotherapy and immunotherapy in the treatment of drug-resistant and/or immunotherapy-resistant /"bladder carcinoma"/. | [
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} | Yes |
9070496 | Doxorubicin sensitizes human bladder carcinoma cells to Fas-mediated cytotoxicity. | BACKGROUND: The resistance of bladder carcinoma to anticancer chemotherapeutic agents remains a major problem. Hence, several immunotherapeutic approaches have been developed to treat the drug-resistant cancer cells. Fas antigen (Fas) and Fas ligand participate in cytotoxicity mediated by T lymphocytes and natural killer cells. Like Fas ligand, anti-Fas monoclonal antibody (MoAb) induces apoptosis of the cells expressing Fas. This study examined whether bladder carcinoma cells are sensitive to cytotoxicity mediated by anti-Fas MoAb and whether anticancer agents synergize with anti-Fas MoAb in cytotoxicity. METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. RESULTS: The T24 human bladder carcinoma cell line constitutively expressed the Fas on the cell surface; however, T24 line was resistant to anti-Fas MoAb. Treatment of T24 cells with anti-Fas MoAb in combination with mitomycin C, methotrexate, or 5-fluorouracil did not overcome their resistance to these agents. However, treatment of T24 cells with a combination of anti-Fas MoAb and doxorubicin resulted in a synergistic cytotoxic effect. In addition, the doxorubicin-resistant T24 cells were sensitive to treatment with a combination of anti-Fas MoAb and doxorubicin. Synergy was also achieved in three other bladder carcinoma cell lines and four freshly derived human bladder carcinoma cells. Treatment with anti-Fas MoAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on T24 cells. The mechanisms of synergy were examined. Anti-Fas MoAb did not affect the intracellular accumulation of doxorubicin, the expression of P-glycoprotein, or the expression of the antioxidant glutathione S-transferase-pi mRNA. However, treatment with doxorubicin enhanced the expression of Fas on T24 cells. CONCLUSIONS: This study demonstrated that treatment of bladder carcinoma cells with doxorubicin sensitized the cells to lysis by anti-Fas MoAb. The synergistic effect obtained with established doxorubicin-resistant bladder carcinoma cells and freshly isolated bladder carcinoma cells suggests that drug-resistant bladder carcinoma cells can be sensitized by doxorubicin to Fas- and Fas ligant-mediated cytotoxicity by lymphocytes. Furthermore, the sensitization required low concentrations of doxorubicin, thus supporting the in vivo application of a combination of chemotherapy and immunotherapy in the treatment of drug-resistant and/or immunotherapy-resistant bladder carcinoma. | Doxorubicin sensitizes human bladder carcinoma cells to Fas-mediated /"cytotoxicity"/. | BACKGROUND: The resistance of bladder carcinoma to anticancer chemotherapeutic agents remains a major problem. Hence, several immunotherapeutic approaches have been developed to treat the drug-resistant cancer cells. Fas antigen (Fas) and Fas ligand participate in /"cytotoxicity"/ mediated by T lymphocytes and natural killer cells. Like Fas ligand, anti-Fas monoclonal antibody (MoAb) induces apoptosis of the cells expressing Fas. This study examined whether bladder carcinoma cells are sensitive to /"cytotoxicity"/ mediated by anti-Fas MoAb and whether anticancer agents synergize with anti-Fas MoAb in /"cytotoxicity"/. METHODS: /"Cytotoxicity"/ was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis. RESULTS: The T24 human bladder carcinoma cell line constitutively expressed the Fas on the cell surface; however, T24 line was resistant to anti-Fas MoAb. Treatment of T24 cells with anti-Fas MoAb in combination with mitomycin C, methotrexate, or 5-fluorouracil did not overcome their resistance to these agents. However, treatment of T24 cells with a combination of anti-Fas MoAb and doxorubicin resulted in a synergistic cytotoxic effect. In addition, the doxorubicin-resistant T24 cells were sensitive to treatment with a combination of anti-Fas MoAb and doxorubicin. Synergy was also achieved in three other bladder carcinoma cell lines and four freshly derived human bladder carcinoma cells. Treatment with anti-Fas MoAb in combination with epirubicin or pirarubicin also resulted in a synergistic cytotoxic effect on T24 cells. The mechanisms of synergy were examined. Anti-Fas MoAb did not affect the intracellular accumulation of doxorubicin, the expression of /"P-glycoprotein"/, or the expression of the antioxidant glutathione S-transferase-pi mRNA. However, treatment with doxorubicin enhanced the expression of Fas on T24 cells. CONCLUSIONS: This study demonstrated that treatment of bladder carcinoma cells with doxorubicin sensitized the cells to lysis by anti-Fas MoAb. The synergistic effect obtained with established doxorubicin-resistant bladder carcinoma cells and freshly isolated bladder carcinoma cells suggests that drug-resistant bladder carcinoma cells can be sensitized by doxorubicin to Fas- and Fas ligant-mediated /"cytotoxicity"/ by lymphocytes. Furthermore, the sensitization required low concentrations of doxorubicin, thus supporting the in vivo application of a combination of chemotherapy and immunotherapy in the treatment of drug-resistant and/or immunotherapy-resistant bladder carcinoma. | [
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9149321 | Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder. | We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder. | Structure of a variable number tandem repeat of the /"serotonin transporter"/ gene and association with /"affective disorder"/. | We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the /"serotonin transporter"/ gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with /"affective disorder"/ and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the /"serotonin transporter"/ gene may contribute to susceptibility for both major depression and bipolar disorder. | [
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9149321 | Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder. | We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder. | Structure of a variable number tandem repeat of the /"serotonin transporter"/ gene and association with affective disorder. | We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the /"serotonin transporter"/ gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with /"bipolar disorder"/ and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for /"bipolar disorder"/ 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the /"serotonin transporter"/ gene may contribute to susceptibility for both major depression and /"bipolar disorder"/. | [
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9158107 | Pathogenicity of human anti-platelet factor 4 (PF4)/heparin in vivo: generation of mouse anti-PF4/heparin and induction of thrombocytopenia by heparin. | Heparin-induced thrombocytopenia/thrombosis (HIT) is a severe thrombotic disorder that occurs in approximately 1% of patients treated with heparin. Affected patients commonly develop antibodies that recognize PF4/heparin complexes that may form on the surface of activated platelets and on the endothelium. However, it has not been established that anti-PF4/heparin antibodies are responsible for the clinical manifestations of HIT. To address this issue, we employed a recently developed model of active immunity to study the effect of IgG anti-PF4/heparin antibody in vivo. In previous studies we have shown that it is possible to induce autoimmune diseases such as systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS) or vasculitis in naive mice by active immunization with anti-DNA, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, respectively. Immunized animals develop anti-idiotypic antibodies (Ab2) and, after 2-4 months, anti-anti-idiotypic antibodies (Ab3). Ab3s generated in this manner often simulate the binding activity of Ab1 and their expression correlates with the development of specific clinical manifestations typical of the respective human disease. Based on this experience, naive BALB/c mice were immunized with IgG anti-PF4/heparin antibodies isolated from two patients with HIT. The actively immunized mice developed mouse anti-PF4/heparin antibody (Ab3). Administration of unfractionated heparin, but not low molecular weight heparin (LMWH), to the actively immunized animals induced thrombocytopenia by day 4 of drug exposure. There was no evidence of thrombosis. The results of this study support the importance of anti-PF4/heparin antibodies in the pathogenesis of HIT. Further, this model may help to elucidate the factors responsible for thrombosis as well as providing means to assess new treatment options for patients with this disorder. | Pathogenicity of human /"anti-platelet factor 4"/ (/"PF4"/)/heparin in vivo: generation of mouse anti-/"PF4"//heparin and induction of /"thrombocytopenia"/ by heparin. | /"Heparin-induced thrombocytopenia/thrombosis"/ (/"HIT"/) is a severe thrombotic disorder that occurs in approximately 1% of patients treated with heparin. Affected patients commonly develop antibodies that recognize /"PF4"//heparin complexes that may form on the surface of activated platelets and on the endothelium. However, it has not been established that anti-/"PF4"//heparin antibodies are responsible for the clinical manifestations of /"HIT"/. To address this issue, we employed a recently developed model of active immunity to study the effect of IgG anti-/"PF4"//heparin antibody in vivo. In previous studies we have shown that it is possible to induce autoimmune diseases such as systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS) or vasculitis in naive mice by active immunization with anti-DNA, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, respectively. Immunized animals develop anti-idiotypic antibodies (Ab2) and, after 2-4 months, anti-anti-idiotypic antibodies (Ab3). Ab3s generated in this manner often simulate the binding activity of Ab1 and their expression correlates with the development of specific clinical manifestations typical of the respective human disease. Based on this experience, naive BALB/c mice were immunized with IgG anti-/"PF4"//heparin antibodies isolated from two patients with /"HIT"/. The actively immunized mice developed mouse anti-/"PF4"//heparin antibody (Ab3). Administration of unfractionated heparin, but not low molecular weight heparin (LMWH), to the actively immunized animals induced /"thrombocytopenia"/ by day 4 of drug exposure. There was no evidence of thrombosis. The results of this study support the importance of anti-/"PF4"//heparin antibodies in the pathogenesis of /"HIT"/. Further, this model may help to elucidate the factors responsible for thrombosis as well as providing means to assess new treatment options for patients with this disorder. | [
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} | Yes |
9158107 | Pathogenicity of human anti-platelet factor 4 (PF4)/heparin in vivo: generation of mouse anti-PF4/heparin and induction of thrombocytopenia by heparin. | Heparin-induced thrombocytopenia/thrombosis (HIT) is a severe thrombotic disorder that occurs in approximately 1% of patients treated with heparin. Affected patients commonly develop antibodies that recognize PF4/heparin complexes that may form on the surface of activated platelets and on the endothelium. However, it has not been established that anti-PF4/heparin antibodies are responsible for the clinical manifestations of HIT. To address this issue, we employed a recently developed model of active immunity to study the effect of IgG anti-PF4/heparin antibody in vivo. In previous studies we have shown that it is possible to induce autoimmune diseases such as systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS) or vasculitis in naive mice by active immunization with anti-DNA, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, respectively. Immunized animals develop anti-idiotypic antibodies (Ab2) and, after 2-4 months, anti-anti-idiotypic antibodies (Ab3). Ab3s generated in this manner often simulate the binding activity of Ab1 and their expression correlates with the development of specific clinical manifestations typical of the respective human disease. Based on this experience, naive BALB/c mice were immunized with IgG anti-PF4/heparin antibodies isolated from two patients with HIT. The actively immunized mice developed mouse anti-PF4/heparin antibody (Ab3). Administration of unfractionated heparin, but not low molecular weight heparin (LMWH), to the actively immunized animals induced thrombocytopenia by day 4 of drug exposure. There was no evidence of thrombosis. The results of this study support the importance of anti-PF4/heparin antibodies in the pathogenesis of HIT. Further, this model may help to elucidate the factors responsible for thrombosis as well as providing means to assess new treatment options for patients with this disorder. | Pathogenicity of human /"anti-platelet factor 4"/ (/"PF4"/)/heparin in vivo: generation of mouse anti-/"PF4"//heparin and induction of thrombocytopenia by heparin. | Heparin-induced thrombocytopenia/thrombosis (HIT) is a severe /"thrombotic disorder"/ that occurs in approximately 1% of patients treated with heparin. Affected patients commonly develop antibodies that recognize /"PF4"//heparin complexes that may form on the surface of activated platelets and on the endothelium. However, it has not been established that anti-/"PF4"//heparin antibodies are responsible for the clinical manifestations of HIT. To address this issue, we employed a recently developed model of active immunity to study the effect of IgG anti-/"PF4"//heparin antibody in vivo. In previous studies we have shown that it is possible to induce autoimmune diseases such as systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS) or vasculitis in naive mice by active immunization with anti-DNA, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, respectively. Immunized animals develop anti-idiotypic antibodies (Ab2) and, after 2-4 months, anti-anti-idiotypic antibodies (Ab3). Ab3s generated in this manner often simulate the binding activity of Ab1 and their expression correlates with the development of specific clinical manifestations typical of the respective human disease. Based on this experience, naive BALB/c mice were immunized with IgG anti-/"PF4"//heparin antibodies isolated from two patients with HIT. The actively immunized mice developed mouse anti-/"PF4"//heparin antibody (Ab3). Administration of unfractionated heparin, but not low molecular weight heparin (LMWH), to the actively immunized animals induced thrombocytopenia by day 4 of drug exposure. There was no evidence of /"thrombosis"/. The results of this study support the importance of anti-/"PF4"//heparin antibodies in the pathogenesis of HIT. Further, this model may help to elucidate the factors responsible for /"thrombosis"/ as well as providing means to assess new treatment options for patients with this disorder. | [
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9197423 | Association of a deletion polymorphism of the angiotensin-converting enzyme gene with left-ventricular hypertrophy in Japanese women with essential hypertension; multicenter study of 1,919 subjects. | The relationship of an insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene to left-ventricular hypertrophy in individuals with essential hypertension (EH) was investigated in a large population of Japanese men and women. The ACE genotype of 762 subjects with EH (425 men and 337 women) and 1,157 healthy controls (604 men and 553 women) was determined by polymerase chain reaction analysis. The distribution of ACE genotypes did not differ significantly between patients with EH and control in both men and women. For women with EH, the DD genotype was positively associated with the thickness of the interventricular septum and inversely associated with the left ventricular end-diastolic dimension, both determined by echocardiography. In contrast, the DD genotype was not associated with any echocardiographic parameter in men with EH. These results indicate that the DD genotype is a risk factor for left-ventricular hypertrophy in Japanese women with EH, but not for Japanese men. | Association of a deletion polymorphism of the /"angiotensin-converting enzyme"/ gene with left-ventricular hypertrophy in Japanese women with /"essential hypertension"/; multicenter study of 1,919 subjects. | The relationship of an insertion/deletion (I/D) polymorphism of the /"angiotensin-converting enzyme"/ (/"ACE"/) gene to left-ventricular hypertrophy in individuals with /"essential hypertension"/ (/"EH"/) was investigated in a large population of Japanese men and women. The /"ACE"/ genotype of 762 subjects with /"EH"/ (425 men and 337 women) and 1,157 healthy controls (604 men and 553 women) was determined by polymerase chain reaction analysis. The distribution of /"ACE"/ genotypes did not differ significantly between patients with /"EH"/ and control in both men and women. For women with /"EH"/, the DD genotype was positively associated with the thickness of the interventricular septum and inversely associated with the left ventricular end-diastolic dimension, both determined by echocardiography. In contrast, the DD genotype was not associated with any echocardiographic parameter in men with /"EH"/. These results indicate that the DD genotype is a risk factor for left-ventricular hypertrophy in Japanese women with /"EH"/, but not for Japanese men. | [
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} | Yes |
9197423 | Association of a deletion polymorphism of the angiotensin-converting enzyme gene with left-ventricular hypertrophy in Japanese women with essential hypertension; multicenter study of 1,919 subjects. | The relationship of an insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene to left-ventricular hypertrophy in individuals with essential hypertension (EH) was investigated in a large population of Japanese men and women. The ACE genotype of 762 subjects with EH (425 men and 337 women) and 1,157 healthy controls (604 men and 553 women) was determined by polymerase chain reaction analysis. The distribution of ACE genotypes did not differ significantly between patients with EH and control in both men and women. For women with EH, the DD genotype was positively associated with the thickness of the interventricular septum and inversely associated with the left ventricular end-diastolic dimension, both determined by echocardiography. In contrast, the DD genotype was not associated with any echocardiographic parameter in men with EH. These results indicate that the DD genotype is a risk factor for left-ventricular hypertrophy in Japanese women with EH, but not for Japanese men. | Association of a deletion polymorphism of the /"angiotensin-converting enzyme"/ gene with left-ventricular hypertrophy in Japanese women with essential hypertension; multicenter study of 1,919 subjects. | The relationship of an insertion/deletion (I/D) polymorphism of the /"angiotensin-converting enzyme"/ (/"ACE"/) gene to left-ventricular hypertrophy in individuals with essential hypertension (EH) was investigated in a large population of Japanese men and women. The /"ACE"/ genotype of 762 subjects with EH (425 men and 337 women) and 1,157 healthy controls (604 men and 553 women) was determined by polymerase chain reaction analysis. The distribution of /"ACE"/ genotypes did not differ significantly between patients with EH and control in both men and women. For women with EH, the /"DD"/ genotype was positively associated with the thickness of the interventricular septum and inversely associated with the left ventricular end-diastolic dimension, both determined by echocardiography. In contrast, the /"DD"/ genotype was not associated with any echocardiographic parameter in men with EH. These results indicate that the /"DD"/ genotype is a risk factor for left-ventricular hypertrophy in Japanese women with EH, but not for Japanese men. | [
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9217972 | Association of EGFR gene amplification and CDKN2 (p16/MTS1) gene deletion in glioblastoma multiforme. | Glioblastoma multiforme (GBM) can be divided into genetic subsets: approximately one-third of GBM, primarily in older adults, have EGFR amplification; another one-third, primarily in younger adults, have TP53 mutation. The majority of GBM also have homozygous deletions of the CDKN2 (p16/MTS1) gene, resulting in cell cycle deregulation and elevated proliferation indices. We evaluated the relationship between CDKN2 deletions and the GBM subsets as defined by EGFR amplification or TP53 mutation in 70 GBM. Twenty-eight cases (40%) had EGFR amplification, 21 (30%) had TP53 mutation, and 21 (30%) had neither change. CDKN2 deletions were present in 36 (51%) GBM. Of the 28 GBM with EGFR amplification, 20 (71%) had CDKN2 deletion (p = 0.0078). The remaining 16 cases with CDKN2 loss were divided between GBM with TP53 mutations (6 cases) and GBM with neither EGFR amplification nor TP53 mutation (10 cases). Thus, CDKN2 deletions occur twice as commonly in GBM with EGFR amplification (71%) than in GBM with TP53 mutation (29%). CDKN2 deletions occurred in GBM from patients somewhat older than those patients with GBM lacking CDKN2 deletion (mean age 53 vs. 48 years). Specifically among GBM with EGFR amplification, those with CDKN2 deletions also occurred in patients slightly older than those few GBM without CDKN2 deletions (mean age 55 vs. 51 years). The presence of CDKN2 deletions in most GBM with EGFR amplification and in generally older patients may provide one explanation for the potentially more aggressive nature of such tumors. | Association of /"EGFR"/ gene amplification and CDKN2 (p16/MTS1) gene deletion in /"glioblastoma"/ multiforme. | /"Glioblastoma multiforme"/ (/"GBM"/) can be divided into genetic subsets: approximately one-third of /"GBM"/, primarily in older adults, have /"EGFR"/ amplification; another one-third, primarily in younger adults, have TP53 mutation. The majority of /"GBM"/ also have homozygous deletions of the CDKN2 (p16/MTS1) gene, resulting in cell cycle deregulation and elevated proliferation indices. We evaluated the relationship between CDKN2 deletions and the /"GBM"/ subsets as defined by /"EGFR"/ amplification or TP53 mutation in 70 /"GBM"/. Twenty-eight cases (40%) had /"EGFR"/ amplification, 21 (30%) had TP53 mutation, and 21 (30%) had neither change. CDKN2 deletions were present in 36 (51%) /"GBM"/. Of the 28 /"GBM"/ with /"EGFR"/ amplification, 20 (71%) had CDKN2 deletion (p = 0.0078). The remaining 16 cases with CDKN2 loss were divided between /"GBM"/ with TP53 mutations (6 cases) and /"GBM"/ with neither /"EGFR"/ amplification nor TP53 mutation (10 cases). Thus, CDKN2 deletions occur twice as commonly in /"GBM"/ with /"EGFR"/ amplification (71%) than in /"GBM"/ with TP53 mutation (29%). CDKN2 deletions occurred in /"GBM"/ from patients somewhat older than those patients with /"GBM"/ lacking CDKN2 deletion (mean age 53 vs. 48 years). Specifically among /"GBM"/ with /"EGFR"/ amplification, those with CDKN2 deletions also occurred in patients slightly older than those few /"GBM"/ without CDKN2 deletions (mean age 55 vs. 51 years). The presence of CDKN2 deletions in most /"GBM"/ with /"EGFR"/ amplification and in generally older patients may provide one explanation for the potentially more aggressive nature of such tumors. | [
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9217972 | Association of EGFR gene amplification and CDKN2 (p16/MTS1) gene deletion in glioblastoma multiforme. | Glioblastoma multiforme (GBM) can be divided into genetic subsets: approximately one-third of GBM, primarily in older adults, have EGFR amplification; another one-third, primarily in younger adults, have TP53 mutation. The majority of GBM also have homozygous deletions of the CDKN2 (p16/MTS1) gene, resulting in cell cycle deregulation and elevated proliferation indices. We evaluated the relationship between CDKN2 deletions and the GBM subsets as defined by EGFR amplification or TP53 mutation in 70 GBM. Twenty-eight cases (40%) had EGFR amplification, 21 (30%) had TP53 mutation, and 21 (30%) had neither change. CDKN2 deletions were present in 36 (51%) GBM. Of the 28 GBM with EGFR amplification, 20 (71%) had CDKN2 deletion (p = 0.0078). The remaining 16 cases with CDKN2 loss were divided between GBM with TP53 mutations (6 cases) and GBM with neither EGFR amplification nor TP53 mutation (10 cases). Thus, CDKN2 deletions occur twice as commonly in GBM with EGFR amplification (71%) than in GBM with TP53 mutation (29%). CDKN2 deletions occurred in GBM from patients somewhat older than those patients with GBM lacking CDKN2 deletion (mean age 53 vs. 48 years). Specifically among GBM with EGFR amplification, those with CDKN2 deletions also occurred in patients slightly older than those few GBM without CDKN2 deletions (mean age 55 vs. 51 years). The presence of CDKN2 deletions in most GBM with EGFR amplification and in generally older patients may provide one explanation for the potentially more aggressive nature of such tumors. | Association of EGFR gene amplification and /"CDKN2"/ (/"p16"///"MTS1"/) gene deletion in /"glioblastoma"/ multiforme. | /"Glioblastoma multiforme"/ (/"GBM"/) can be divided into genetic subsets: approximately one-third of /"GBM"/, primarily in older adults, have EGFR amplification; another one-third, primarily in younger adults, have TP53 mutation. The majority of /"GBM"/ also have homozygous deletions of the /"CDKN2"/ (/"p16"///"MTS1"/) gene, resulting in cell cycle deregulation and elevated proliferation indices. We evaluated the relationship between /"CDKN2"/ deletions and the /"GBM"/ subsets as defined by EGFR amplification or TP53 mutation in 70 /"GBM"/. Twenty-eight cases (40%) had EGFR amplification, 21 (30%) had TP53 mutation, and 21 (30%) had neither change. /"CDKN2"/ deletions were present in 36 (51%) /"GBM"/. Of the 28 /"GBM"/ with EGFR amplification, 20 (71%) had /"CDKN2"/ deletion (p = 0.0078). The remaining 16 cases with /"CDKN2"/ loss were divided between /"GBM"/ with TP53 mutations (6 cases) and /"GBM"/ with neither EGFR amplification nor TP53 mutation (10 cases). Thus, /"CDKN2"/ deletions occur twice as commonly in /"GBM"/ with EGFR amplification (71%) than in /"GBM"/ with TP53 mutation (29%). /"CDKN2"/ deletions occurred in /"GBM"/ from patients somewhat older than those patients with /"GBM"/ lacking /"CDKN2"/ deletion (mean age 53 vs. 48 years). Specifically among /"GBM"/ with EGFR amplification, those with /"CDKN2"/ deletions also occurred in patients slightly older than those few /"GBM"/ without /"CDKN2"/ deletions (mean age 55 vs. 51 years). The presence of /"CDKN2"/ deletions in most /"GBM"/ with EGFR amplification and in generally older patients may provide one explanation for the potentially more aggressive nature of such tumors. | [
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9236417 | D allele of the angiotensin I-converting enzyme is a major risk factor for restenosis after coronary stenting. | BACKGROUND: Although intracoronary stent implantation significantly reduces restenosis compared with balloon angioplasty, a minority of patients still develop restenosis predominantly due to neointimal hyperplasia. Experimental studies suggest that the renin-angiotensin system is involved in neointimal hyperplasia after arterial injury. In humans, the plasma and cellular levels of ACE are associated with an I/D genetic polymorphism in the ACE gene, DD patients having higher levels. METHODS AND RESULTS: We investigated a possible relation between the ACE I/D polymorphism and restenosis in 146 patients who underwent successful implantation of a Palmaz-Schatz stent and had 6-month follow-up angiography. The minimal lumen diameter (MLD) before and after the procedure did not differ significantly among the three groups of genotypes (DD, ID, and II). At follow-up, MLD had a significant inverse relationship to the number of D alleles present (DD, 1.65 +/- 0.71 mm; ID, 1.84 +/- 0.60 mm; II, 2.05 +/- 0.61 mm; P < .007). Late luminal loss during the follow-up period was significantly related to the number of D alleles (DD, 0.89 +/- 0.61 mm; ID, 0.60 +/- 0.52 mm; II, 0.40 +/- 0.53 mm; P < .0001). The relative risk of restenosis (defined as a > 50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of D alleles (95% confidence interval, 1.03 to 3.88, P < .04). CONCLUSIONS: The ACE I/D polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the renin-angiotensin system may be implicated in the pathogenesis of restenosis after coronary stenting. | D allele of the angiotensin I-converting enzyme is a major risk factor for /"restenosis"/ after coronary stenting. | BACKGROUND: Although intracoronary stent implantation significantly reduces /"restenosis"/ compared with balloon angioplasty, a minority of patients still develop /"restenosis"/ predominantly due to neointimal hyperplasia. Experimental studies suggest that the renin-angiotensin system is involved in neointimal hyperplasia after arterial injury. In humans, the plasma and cellular levels of /"ACE"/ are associated with an I/D genetic polymorphism in the /"ACE"/ gene, DD patients having higher levels. METHODS AND RESULTS: We investigated a possible relation between the /"ACE"/ I/D polymorphism and /"restenosis"/ in 146 patients who underwent successful implantation of a Palmaz-Schatz stent and had 6-month follow-up angiography. The minimal lumen diameter (MLD) before and after the procedure did not differ significantly among the three groups of genotypes (DD, ID, and II). At follow-up, MLD had a significant inverse relationship to the number of D alleles present (DD, 1.65 +/- 0.71 mm; ID, 1.84 +/- 0.60 mm; II, 2.05 +/- 0.61 mm; P < .007). Late luminal loss during the follow-up period was significantly related to the number of D alleles (DD, 0.89 +/- 0.61 mm; ID, 0.60 +/- 0.52 mm; II, 0.40 +/- 0.53 mm; P < .0001). The relative risk of /"restenosis"/ (defined as a > 50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of D alleles (95% confidence interval, 1.03 to 3.88, P < .04). CONCLUSIONS: The /"ACE"/ I/D polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the renin-angiotensin system may be implicated in the pathogenesis of /"restenosis"/ after coronary stenting. | [
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} | {
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"end_idx": "85",
"entity_id": "D023903",
"entity_type": "Disease",
"text_name": "restenosis"
} | Yes |
9236417 | D allele of the angiotensin I-converting enzyme is a major risk factor for restenosis after coronary stenting. | BACKGROUND: Although intracoronary stent implantation significantly reduces restenosis compared with balloon angioplasty, a minority of patients still develop restenosis predominantly due to neointimal hyperplasia. Experimental studies suggest that the renin-angiotensin system is involved in neointimal hyperplasia after arterial injury. In humans, the plasma and cellular levels of ACE are associated with an I/D genetic polymorphism in the ACE gene, DD patients having higher levels. METHODS AND RESULTS: We investigated a possible relation between the ACE I/D polymorphism and restenosis in 146 patients who underwent successful implantation of a Palmaz-Schatz stent and had 6-month follow-up angiography. The minimal lumen diameter (MLD) before and after the procedure did not differ significantly among the three groups of genotypes (DD, ID, and II). At follow-up, MLD had a significant inverse relationship to the number of D alleles present (DD, 1.65 +/- 0.71 mm; ID, 1.84 +/- 0.60 mm; II, 2.05 +/- 0.61 mm; P < .007). Late luminal loss during the follow-up period was significantly related to the number of D alleles (DD, 0.89 +/- 0.61 mm; ID, 0.60 +/- 0.52 mm; II, 0.40 +/- 0.53 mm; P < .0001). The relative risk of restenosis (defined as a > 50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of D alleles (95% confidence interval, 1.03 to 3.88, P < .04). CONCLUSIONS: The ACE I/D polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the renin-angiotensin system may be implicated in the pathogenesis of restenosis after coronary stenting. | D allele of the angiotensin I-converting enzyme is a major risk factor for /"restenosis"/ after coronary stenting. | BACKGROUND: Although intracoronary stent implantation significantly reduces /"restenosis"/ compared with balloon angioplasty, a minority of patients still develop /"restenosis"/ predominantly due to neointimal hyperplasia. Experimental studies suggest that the /"renin"/-angiotensin system is involved in neointimal hyperplasia after arterial injury. In humans, the plasma and cellular levels of ACE are associated with an I/D genetic polymorphism in the ACE gene, DD patients having higher levels. METHODS AND RESULTS: We investigated a possible relation between the ACE I/D polymorphism and /"restenosis"/ in 146 patients who underwent successful implantation of a Palmaz-Schatz stent and had 6-month follow-up angiography. The minimal lumen diameter (MLD) before and after the procedure did not differ significantly among the three groups of genotypes (DD, ID, and II). At follow-up, MLD had a significant inverse relationship to the number of D alleles present (DD, 1.65 +/- 0.71 mm; ID, 1.84 +/- 0.60 mm; II, 2.05 +/- 0.61 mm; P < .007). Late luminal loss during the follow-up period was significantly related to the number of D alleles (DD, 0.89 +/- 0.61 mm; ID, 0.60 +/- 0.52 mm; II, 0.40 +/- 0.53 mm; P < .0001). The relative risk of /"restenosis"/ (defined as a > 50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of D alleles (95% confidence interval, 1.03 to 3.88, P < .04). CONCLUSIONS: The ACE I/D polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the /"renin"/-angiotensin system may be implicated in the pathogenesis of /"restenosis"/ after coronary stenting. | [
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"text_name": "minimal lumen diameter"
},
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},
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"entity_type": "Disease",
"text_name": "arterial injury"
},
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},
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"text_name": "renin"
}
] | {
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"entity_type": "Gene",
"text_name": "renin"
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"end_idx": "1745",
"entity_id": "D023903",
"entity_type": "Disease",
"text_name": "restenosis"
} | No |
9360549 | Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita. | The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291 Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child. | Three novel mutations and a de novo deletion mutation of the /"DAX-1"/ gene in patients with /"X-linked adrenal hypoplasia congenita"/. | The /"DAX-1"/ [DSS (dosage sensitive sex)-/"AHC"/ critical region on the X, gene 1] gene is responsible for /"X-linked adrenal hypoplasia congenita"/ (/"AHC"/). However, /"DAX-1"/ protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the /"DAX-1"/ gene from seven patients in six kindreds with /"X-linked AHC"/ and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291 Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human /"DAX-1"/ protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the /"DAX-1"/ protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the /"DAX-1"/ gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child. | [
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}
] | {
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"text_name": "DAX-1"
} | {
"begin_idx": "89",
"end_idx": "126",
"entity_id": "C536757",
"entity_type": "Disease",
"text_name": "X-linked adrenal hypoplasia congenita"
} | Yes |
9361298 | Connexin32 and X-linked Charcot-Marie-Tooth disease. | Mutations in the gap junction gene connexin32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. More than 130 different mutations have been described, affecting all portions of the Cx32 protein. In transfected cells, the mutant Cx32 proteins encoded by some Cx32 mutations fall to reach the cell surface; other mutant proteins reach the cell surface, but only one of these forms functional gap junctions. In peripheral nerve, Cx32 is localized to incisures and paranodes, regions of noncompact myelin within the myelin sheath. This localization suggests that Cx32 forms "reflexive" gap junctions that allow ions and small molecules to diffuse directly across the myelin sheath, which is a thousandfold shorter distance than the circumferential pathway through the Schwann cell cytoplasm. Cx32 mutations may interrupt this shorter pathway or have other toxic effects, thereby injuring myelinating Schwann cells and their axons. | /"Connexin32"/ and /"X-linked Charcot-Marie-Tooth disease"/. | Mutations in the gap junction gene /"connexin32"/ (/"Cx32"/) cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. More than 130 different mutations have been described, affecting all portions of the /"Cx32"/ protein. In transfected cells, the mutant /"Cx32"/ proteins encoded by some /"Cx32"/ mutations fall to reach the cell surface; other mutant proteins reach the cell surface, but only one of these forms functional gap junctions. In peripheral nerve, /"Cx32"/ is localized to incisures and paranodes, regions of noncompact myelin within the myelin sheath. This localization suggests that /"Cx32"/ forms "reflexive" gap junctions that allow ions and small molecules to diffuse directly across the myelin sheath, which is a thousandfold shorter distance than the circumferential pathway through the Schwann cell cytoplasm. /"Cx32"/ mutations may interrupt this shorter pathway or have other toxic effects, thereby injuring myelinating Schwann cells and their axons. | [
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"entity_type": "Disease",
"text_name": "X-linked Charcot-Marie-Tooth disease"
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"entity_id": "D002607",
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},
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"text_name": "inherited demyelinating neuropathy"
},
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"entity_type": "Disease",
"text_name": "myelin sheath"
},
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"text_name": "myelin sheath"
},
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"text_name": "Connexin32"
},
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"text_name": "connexin32"
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},
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"entity_type": "Gene",
"text_name": "Cx32"
},
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"entity_type": "Gene",
"text_name": "Cx32"
},
{
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"entity_id": "2705",
"entity_type": "Gene",
"text_name": "Cx32"
}
] | {
"begin_idx": "0",
"end_idx": "10",
"entity_id": "2705",
"entity_type": "Gene",
"text_name": "Connexin32"
} | {
"begin_idx": "15",
"end_idx": "51",
"entity_id": "C535919",
"entity_type": "Disease",
"text_name": "X-linked Charcot-Marie-Tooth disease"
} | Yes |
9361298 | Connexin32 and X-linked Charcot-Marie-Tooth disease. | Mutations in the gap junction gene connexin32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. More than 130 different mutations have been described, affecting all portions of the Cx32 protein. In transfected cells, the mutant Cx32 proteins encoded by some Cx32 mutations fall to reach the cell surface; other mutant proteins reach the cell surface, but only one of these forms functional gap junctions. In peripheral nerve, Cx32 is localized to incisures and paranodes, regions of noncompact myelin within the myelin sheath. This localization suggests that Cx32 forms "reflexive" gap junctions that allow ions and small molecules to diffuse directly across the myelin sheath, which is a thousandfold shorter distance than the circumferential pathway through the Schwann cell cytoplasm. Cx32 mutations may interrupt this shorter pathway or have other toxic effects, thereby injuring myelinating Schwann cells and their axons. | /"Connexin32"/ and X-linked Charcot-Marie-Tooth disease. | Mutations in the gap junction gene /"connexin32"/ (/"Cx32"/) cause the X-linked form of Charcot-Marie-Tooth disease, an /"inherited demyelinating neuropathy"/. More than 130 different mutations have been described, affecting all portions of the /"Cx32"/ protein. In transfected cells, the mutant /"Cx32"/ proteins encoded by some /"Cx32"/ mutations fall to reach the cell surface; other mutant proteins reach the cell surface, but only one of these forms functional gap junctions. In peripheral nerve, /"Cx32"/ is localized to incisures and paranodes, regions of noncompact myelin within the /"myelin sheath"/. This localization suggests that /"Cx32"/ forms "reflexive" gap junctions that allow ions and small molecules to diffuse directly across the /"myelin sheath"/, which is a thousandfold shorter distance than the circumferential pathway through the Schwann cell cytoplasm. /"Cx32"/ mutations may interrupt this shorter pathway or have other toxic effects, thereby injuring myelinating Schwann cells and their axons. | [
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},
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},
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},
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"text_name": "myelin sheath"
},
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},
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},
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},
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"text_name": "Cx32"
},
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"text_name": "Cx32"
},
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"text_name": "Cx32"
},
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"text_name": "Cx32"
},
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"entity_type": "Gene",
"text_name": "Cx32"
},
{
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"end_idx": "668",
"entity_id": "2705",
"entity_type": "Gene",
"text_name": "Cx32"
},
{
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"end_idx": "897",
"entity_id": "2705",
"entity_type": "Gene",
"text_name": "Cx32"
}
] | {
"begin_idx": "531",
"end_idx": "535",
"entity_id": "2705",
"entity_type": "Gene",
"text_name": "Cx32"
} | {
"begin_idx": "165",
"end_idx": "199",
"entity_id": "D003711",
"entity_type": "Disease",
"text_name": "inherited demyelinating neuropathy"
} | No |
9382152 | Two new missense mutations (A105T and C110G) in the norrin gene in two Italian families with Norrie disease and familial exudative vitreoretinopathy. | Two new missense mutations (A105T and C110G) in the /"norrin"/ gene in two Italian families with /"Norrie disease"/ and familial exudative vitreoretinopathy. | [
{
"begin_idx": "93",
"end_idx": "107",
"entity_id": "C537849",
"entity_type": "Disease",
"text_name": "Norrie disease"
},
{
"begin_idx": "112",
"end_idx": "148",
"entity_id": "C580083",
"entity_type": "Disease",
"text_name": "familial exudative vitreoretinopathy"
},
{
"begin_idx": "52",
"end_idx": "58",
"entity_id": "4693",
"entity_type": "Gene",
"text_name": "norrin"
}
] | {
"begin_idx": "52",
"end_idx": "58",
"entity_id": "4693",
"entity_type": "Gene",
"text_name": "norrin"
} | {
"begin_idx": "93",
"end_idx": "107",
"entity_id": "C537849",
"entity_type": "Disease",
"text_name": "Norrie disease"
} | Yes |
||
9382152 | Two new missense mutations (A105T and C110G) in the norrin gene in two Italian families with Norrie disease and familial exudative vitreoretinopathy. | Two new missense mutations (A105T and C110G) in the /"norrin"/ gene in two Italian families with Norrie disease and /"familial exudative vitreoretinopathy"/. | [
{
"begin_idx": "93",
"end_idx": "107",
"entity_id": "C537849",
"entity_type": "Disease",
"text_name": "Norrie disease"
},
{
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"end_idx": "148",
"entity_id": "C580083",
"entity_type": "Disease",
"text_name": "familial exudative vitreoretinopathy"
},
{
"begin_idx": "52",
"end_idx": "58",
"entity_id": "4693",
"entity_type": "Gene",
"text_name": "norrin"
}
] | {
"begin_idx": "52",
"end_idx": "58",
"entity_id": "4693",
"entity_type": "Gene",
"text_name": "norrin"
} | {
"begin_idx": "112",
"end_idx": "148",
"entity_id": "C580083",
"entity_type": "Disease",
"text_name": "familial exudative vitreoretinopathy"
} | No |
||
9391065 | Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active rhodopsin mutants found in patients with autosomal dominant retinitis pigmentosa. | Two different mutations of the active-site Lys-296 in rhodopsin, K296E and K296M, have been found to cause autosomal dominant retinitis pigmentosa (ADRP). In vitro studies have shown that both mutations result in constitutive activation of the protein, suggesting that the activated state of the receptor may be responsible for retinal degeneration in patients with these mutations. Previous work has highlighted the potential of retinylamine analogs as active-site directed inactivators of constitutively active mutants of rhodopsin with the idea that these or related compounds might be used therapeutically for cases of ADRP involving mutations of the active-site Lys. Unfortunately, however, amine derivatives of 11-cis-retinal, although highly effective against a K296G mutant of rhodopsin, were without affect on the two naturally occurring ADRP mutants, presumably because of the greater steric bulk of Glu and Met side chains in comparison to Gly. For this reason we synthesized a retinylamine analog one carbon shorter than the parent 11-cis-retinal and show that this compound is indeed an effective inhibitor of both the K296E and K296M mutants. The 11-cis C19 retinylamine analog 1 inhibits constitutive activation of transducin by these mutants and their constitutive phosphorylation by rhodopsin kinase, and it does so in the presence of continuous illumination from room lights. | Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active /"rhodopsin"/ mutants found in patients with /"autosomal dominant retinitis pigmentosa"/. | Two different mutations of the active-site Lys-296 in /"rhodopsin"/, K296E and K296M, have been found to cause /"autosomal dominant retinitis pigmentosa"/ (/"ADRP"/). In vitro studies have shown that both mutations result in constitutive activation of the protein, suggesting that the activated state of the receptor may be responsible for retinal degeneration in patients with these mutations. Previous work has highlighted the potential of retinylamine analogs as active-site directed inactivators of constitutively active mutants of /"rhodopsin"/ with the idea that these or related compounds might be used therapeutically for cases of /"ADRP"/ involving mutations of the active-site Lys. Unfortunately, however, amine derivatives of 11-cis-retinal, although highly effective against a K296G mutant of /"rhodopsin"/, were without affect on the two naturally occurring /"ADRP"/ mutants, presumably because of the greater steric bulk of Glu and Met side chains in comparison to Gly. For this reason we synthesized a retinylamine analog one carbon shorter than the parent 11-cis-retinal and show that this compound is indeed an effective inhibitor of both the K296E and K296M mutants. The 11-cis C19 retinylamine analog 1 inhibits constitutive activation of transducin by these mutants and their constitutive phosphorylation by /"rhodopsin"/ kinase, and it does so in the presence of continuous illumination from room lights. | [
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9391065 | Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active rhodopsin mutants found in patients with autosomal dominant retinitis pigmentosa. | Two different mutations of the active-site Lys-296 in rhodopsin, K296E and K296M, have been found to cause autosomal dominant retinitis pigmentosa (ADRP). In vitro studies have shown that both mutations result in constitutive activation of the protein, suggesting that the activated state of the receptor may be responsible for retinal degeneration in patients with these mutations. Previous work has highlighted the potential of retinylamine analogs as active-site directed inactivators of constitutively active mutants of rhodopsin with the idea that these or related compounds might be used therapeutically for cases of ADRP involving mutations of the active-site Lys. Unfortunately, however, amine derivatives of 11-cis-retinal, although highly effective against a K296G mutant of rhodopsin, were without affect on the two naturally occurring ADRP mutants, presumably because of the greater steric bulk of Glu and Met side chains in comparison to Gly. For this reason we synthesized a retinylamine analog one carbon shorter than the parent 11-cis-retinal and show that this compound is indeed an effective inhibitor of both the K296E and K296M mutants. The 11-cis C19 retinylamine analog 1 inhibits constitutive activation of transducin by these mutants and their constitutive phosphorylation by rhodopsin kinase, and it does so in the presence of continuous illumination from room lights. | Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active /"rhodopsin"/ mutants found in patients with autosomal dominant retinitis pigmentosa. | Two different mutations of the active-site Lys-296 in /"rhodopsin"/, K296E and K296M, have been found to cause autosomal dominant retinitis pigmentosa (ADRP). In vitro studies have shown that both mutations result in constitutive activation of the protein, suggesting that the activated state of the receptor may be responsible for /"retinal degeneration"/ in patients with these mutations. Previous work has highlighted the potential of retinylamine analogs as active-site directed inactivators of constitutively active mutants of /"rhodopsin"/ with the idea that these or related compounds might be used therapeutically for cases of ADRP involving mutations of the active-site Lys. Unfortunately, however, amine derivatives of 11-cis-retinal, although highly effective against a K296G mutant of /"rhodopsin"/, were without affect on the two naturally occurring ADRP mutants, presumably because of the greater steric bulk of Glu and Met side chains in comparison to Gly. For this reason we synthesized a retinylamine analog one carbon shorter than the parent 11-cis-retinal and show that this compound is indeed an effective inhibitor of both the K296E and K296M mutants. The 11-cis C19 retinylamine analog 1 inhibits constitutive activation of transducin by these mutants and their constitutive phosphorylation by /"rhodopsin"/ kinase, and it does so in the presence of continuous illumination from room lights. | [
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9475597 | Distribution of (CGG)n and FMR-1 associated microsatellite alleles in a normal Chilean population. | We report on the allele distribution in a normal Chilean population at 2 microsatellite loci neighbouring the FRAXA locus and at the CGG repeat in the 5' end of the FMR-1 gene, which causes the fragile X syndrome. The most common CGG repeat allele was 30 (41.7%), with 29 being second most common (30.2%). This distribution was similar from that seen in Caucasians but different from that observed in Chinese controls, where the most common allele was 29 repeats. Four alleles of FRAXAC1 and 6 of DXS548 were observed in the Chilean sample. A striking linkage disequilibrium of FMR-1 alleles with FRAXAC1 alleles was observed. In 90% of the 30 CGG repeat alleles only 31% of the 29 CGG repeat alleles had the FRAXAC1 154 bp allele. This result is in agreement with the suggestion that slippage between CGG repeat alleles 29 and 30 and between 152 and 154 FRAXAC1 alleles is very rare. This study suggests a founder chromosome effect in the Chilean population. | Distribution of (CGG)n and /"FMR-1"/ associated microsatellite alleles in a normal Chilean population. | We report on the allele distribution in a normal Chilean population at 2 microsatellite loci neighbouring the FRAXA locus and at the CGG repeat in the 5' end of the /"FMR-1"/ gene, which causes the /"fragile X syndrome"/. The most common CGG repeat allele was 30 (41.7%), with 29 being second most common (30.2%). This distribution was similar from that seen in Caucasians but different from that observed in Chinese controls, where the most common allele was 29 repeats. Four alleles of FRAXAC1 and 6 of DXS548 were observed in the Chilean sample. A striking linkage disequilibrium of /"FMR-1"/ alleles with FRAXAC1 alleles was observed. In 90% of the 30 CGG repeat alleles only 31% of the 29 CGG repeat alleles had the FRAXAC1 154 bp allele. This result is in agreement with the suggestion that slippage between CGG repeat alleles 29 and 30 and between 152 and 154 FRAXAC1 alleles is very rare. This study suggests a founder chromosome effect in the Chilean population. | [
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} | Yes |
9475597 | Distribution of (CGG)n and FMR-1 associated microsatellite alleles in a normal Chilean population. | We report on the allele distribution in a normal Chilean population at 2 microsatellite loci neighbouring the FRAXA locus and at the CGG repeat in the 5' end of the FMR-1 gene, which causes the fragile X syndrome. The most common CGG repeat allele was 30 (41.7%), with 29 being second most common (30.2%). This distribution was similar from that seen in Caucasians but different from that observed in Chinese controls, where the most common allele was 29 repeats. Four alleles of FRAXAC1 and 6 of DXS548 were observed in the Chilean sample. A striking linkage disequilibrium of FMR-1 alleles with FRAXAC1 alleles was observed. In 90% of the 30 CGG repeat alleles only 31% of the 29 CGG repeat alleles had the FRAXAC1 154 bp allele. This result is in agreement with the suggestion that slippage between CGG repeat alleles 29 and 30 and between 152 and 154 FRAXAC1 alleles is very rare. This study suggests a founder chromosome effect in the Chilean population. | Distribution of (CGG)n and FMR-1 associated microsatellite alleles in a normal Chilean population. | We report on the allele distribution in a normal Chilean population at 2 microsatellite loci neighbouring the /"FRAXA"/ locus and at the CGG repeat in the 5' end of the FMR-1 gene, which causes the /"fragile X syndrome"/. The most common CGG repeat allele was 30 (41.7%), with 29 being second most common (30.2%). This distribution was similar from that seen in Caucasians but different from that observed in Chinese controls, where the most common allele was 29 repeats. Four alleles of FRAXAC1 and 6 of DXS548 were observed in the Chilean sample. A striking linkage disequilibrium of FMR-1 alleles with FRAXAC1 alleles was observed. In 90% of the 30 CGG repeat alleles only 31% of the 29 CGG repeat alleles had the FRAXAC1 154 bp allele. This result is in agreement with the suggestion that slippage between CGG repeat alleles 29 and 30 and between 152 and 154 FRAXAC1 alleles is very rare. This study suggests a founder chromosome effect in the Chilean population. | [
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9481718 | ApoE polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of nephropathy in NIDDM? | BACKGROUND: Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of nephropathy in insulin dependent diabetes mellitus (IDDM). In contrast, nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) presents with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patent hyperglycaemia. The role of lipid abnormalities in this matter remains debated. METHODS: We studied the prevalence of nephropathy (N+ = urinary albumin excretion rate (UAE) > 20 mg/d) in 134 Caucasian NIDDM patients ranked according to alipoprotein E (apoE) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n = 1) was excluded from the analysis. RESULTS: The prevalence of nephropathy was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P < 0.01). Relative risk (RR) of E2 carriers developing nephropathy was 0.52 (95% CI = 0.35-0.80). Both groups were comparable in terms of age (55 +/- 11 vs 57 +/- 11 years), diabetes duration (15 +/- 9 vs 14 +/- 10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n = 94). CONCLUSIONS: It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of nephropathy in E2 non-carriers with NIDDM argues for a role for LDL in the development of human nephropathy in NIDDM patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between kidney disease and atherosclerosis in NIDDM patients. | /"ApoE"/ polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of nephropathy in /"NIDDM"/? | BACKGROUND: Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of nephropathy in insulin dependent diabetes mellitus (IDDM). In contrast, nephropathy in /"non-insulin-dependent diabetes mellitus"/ (/"NIDDM"/) presents with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patent hyperglycaemia. The role of lipid abnormalities in this matter remains debated. METHODS: We studied the prevalence of nephropathy (N+ = urinary albumin excretion rate (UAE) > 20 mg/d) in 134 Caucasian /"NIDDM"/ patients ranked according to /"alipoprotein E"/ (/"apoE"/) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n = 1) was excluded from the analysis. RESULTS: The prevalence of nephropathy was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P < 0.01). Relative risk (RR) of E2 carriers developing nephropathy was 0.52 (95% CI = 0.35-0.80). Both groups were comparable in terms of age (55 +/- 11 vs 57 +/- 11 years), diabetes duration (15 +/- 9 vs 14 +/- 10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n = 94). CONCLUSIONS: It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of nephropathy in E2 non-carriers with /"NIDDM"/ argues for a role for LDL in the development of human nephropathy in /"NIDDM"/ patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between kidney disease and atherosclerosis in /"NIDDM"/ patients. | [
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"text_name": "non-insulin-dependent diabetes mellitus"
} | Yes |
9481718 | ApoE polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of nephropathy in NIDDM? | BACKGROUND: Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of nephropathy in insulin dependent diabetes mellitus (IDDM). In contrast, nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) presents with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patent hyperglycaemia. The role of lipid abnormalities in this matter remains debated. METHODS: We studied the prevalence of nephropathy (N+ = urinary albumin excretion rate (UAE) > 20 mg/d) in 134 Caucasian NIDDM patients ranked according to alipoprotein E (apoE) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n = 1) was excluded from the analysis. RESULTS: The prevalence of nephropathy was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P < 0.01). Relative risk (RR) of E2 carriers developing nephropathy was 0.52 (95% CI = 0.35-0.80). Both groups were comparable in terms of age (55 +/- 11 vs 57 +/- 11 years), diabetes duration (15 +/- 9 vs 14 +/- 10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n = 94). CONCLUSIONS: It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of nephropathy in E2 non-carriers with NIDDM argues for a role for LDL in the development of human nephropathy in NIDDM patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between kidney disease and atherosclerosis in NIDDM patients. | /"ApoE"/ polymorphism and albuminuria in diabetes mellitus: a role for LDL in the development of /"nephropathy"/ in NIDDM? | BACKGROUND: Chronic hyperglycaemia stands with diabetes duration as the main predicting factor for the development of /"nephropathy"/ in insulin dependent diabetes mellitus (IDDM). In contrast, /"nephropathy"/ in non-insulin-dependent diabetes mellitus (NIDDM) presents with a different natural history and, as well as atherosclerosis, can precede diabetes diagnosis and even the onset of patent hyperglycaemia. The role of lipid abnormalities in this matter remains debated. METHODS: We studied the prevalence of /"nephropathy"/ (N+ = urinary albumin excretion rate (UAE) > 20 mg/d) in 134 Caucasian NIDDM patients ranked according to /"alipoprotein E"/ (/"apoE"/) genotype (same distribution in 132 controls). Age, diabetes duration and sex ratio did not differ between N+ and N-. A patient with E2E4 (n = 1) was excluded from the analysis. RESULTS: The prevalence of /"nephropathy"/ was significantly reduced in E2 allele carriers (36%, 8/22) vs 69% (77/111) in E2 non-carriers (P < 0.01). Relative risk (RR) of E2 carriers developing /"nephropathy"/ was 0.52 (95% CI = 0.35-0.80). Both groups were comparable in terms of age (55 +/- 11 vs 57 +/- 11 years), diabetes duration (15 +/- 9 vs 14 +/- 10 years) and prevalence of retinopathy (59 vs 48%). Similar results were observed when patients with diabetes duration longer than 8 years were studied (n = 94). CONCLUSIONS: It has been largely established that low-density lipoprotein (LDL)-cholesterol level in E2 allele carriers (whether diabetic or not) was lower than in E2 non-carriers. The 2-fold increase of /"nephropathy"/ in E2 non-carriers with NIDDM argues for a role for LDL in the development of human /"nephropathy"/ in NIDDM patients. This result is in agreement with previous data established both in vitro and in vivo in animal models. These findings support evidence for the pathogenic and morphologic similarities between /"kidney disease"/ and atherosclerosis in NIDDM patients. | [
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9498099 | A novel Glu421Lys substitution in the lipoprotein lipase gene in pregnancy-induced hypertriglyceridemic pancreatitis. | Severe hypertriglyceridemia is an uncommon pathological finding in pregnant women if there is no prior history of hyperlipidemia. A partial reduction in lipoprotein lipase (LPL) activity due to a mutation in the LPL gene, is often an associating factor. Here we report a novel LPL gene mutation (Glu421Lys), in a previously healthy primigravid woman who died from hypertriglyceridemia-induced pancreatitis during the last trimester of pregnancy. The patient was heterozygous for this mutation which a charge inversion in the C-terminal domain of LPL resulting in a moderate reduction in catalytic activity, both in vivo and in vitro. These data support the role of partial LPL deficiency in the pathogenesis of severe gestational hypertriglyceridemia. | A novel Glu421Lys substitution in the /"lipoprotein lipase"/ gene in pregnancy-induced hypertriglyceridemic pancreatitis. | Severe hypertriglyceridemia is an uncommon pathological finding in pregnant women if there is no prior history of hyperlipidemia. A partial reduction in /"lipoprotein lipase"/ (/"LPL"/) activity due to a mutation in the /"LPL"/ gene, is often an associating factor. Here we report a novel /"LPL"/ gene mutation (Glu421Lys), in a previously healthy primigravid woman who died from hypertriglyceridemia-induced pancreatitis during the last trimester of pregnancy. The patient was heterozygous for this mutation which a charge inversion in the C-terminal domain of /"LPL"/ resulting in a moderate reduction in catalytic activity, both in vivo and in vitro. These data support the role of partial /"LPL deficiency"/ in the pathogenesis of severe gestational hypertriglyceridemia. | [
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9498099 | A novel Glu421Lys substitution in the lipoprotein lipase gene in pregnancy-induced hypertriglyceridemic pancreatitis. | Severe hypertriglyceridemia is an uncommon pathological finding in pregnant women if there is no prior history of hyperlipidemia. A partial reduction in lipoprotein lipase (LPL) activity due to a mutation in the LPL gene, is often an associating factor. Here we report a novel LPL gene mutation (Glu421Lys), in a previously healthy primigravid woman who died from hypertriglyceridemia-induced pancreatitis during the last trimester of pregnancy. The patient was heterozygous for this mutation which a charge inversion in the C-terminal domain of LPL resulting in a moderate reduction in catalytic activity, both in vivo and in vitro. These data support the role of partial LPL deficiency in the pathogenesis of severe gestational hypertriglyceridemia. | A novel Glu421Lys substitution in the /"lipoprotein lipase"/ gene in pregnancy-induced hypertriglyceridemic /"pancreatitis"/. | Severe hypertriglyceridemia is an uncommon pathological finding in pregnant women if there is no prior history of hyperlipidemia. A partial reduction in /"lipoprotein lipase"/ (/"LPL"/) activity due to a mutation in the /"LPL"/ gene, is often an associating factor. Here we report a novel /"LPL"/ gene mutation (Glu421Lys), in a previously healthy primigravid woman who died from hypertriglyceridemia-induced /"pancreatitis"/ during the last trimester of pregnancy. The patient was heterozygous for this mutation which a charge inversion in the C-terminal domain of /"LPL"/ resulting in a moderate reduction in catalytic activity, both in vivo and in vitro. These data support the role of partial LPL deficiency in the pathogenesis of severe gestational hypertriglyceridemia. | [
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9521595 | Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). | In order to determine the spectrum of cystic fibrosis (CF) mutations in the Turkish population, a complete coding region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene including exon-intron boundaries, on 122 unrelated CF chromosomes from 73 Turkish CF families was analysed by denaturing gradient gel electrophoresis and multiplex heteroduplex analysis on MDE gel matrix. In addition to 15 previously reported mutations and 12 polymorphisms, three novel mutations, namely 3172delAC, P1013L and M1028I, were detected. DeltaF508 was found to be present on 18.8% of CF chromosomes. The second most common mutation was 1677delTA, with a frequency of 7.3%, followed by G542X and 2183AA-->G mutations, with frequencies of 4.9%. These four most common mutations in Turkish CF population account for approximately 36% of mutations. This study could only detect 52.5% of disease-causing mutations in this population; 47.5% of CF alleles remain to be identified, reflecting the high molecular heterogeneity of the Turkish population. | Analysis of the /"CFTR"/ gene in Turkish /"cystic fibrosis"/ patients: identification of three novel mutations (3172delAC, P1013L and M1028I). | In order to determine the spectrum of /"cystic fibrosis"/ (/"CF"/) mutations in the Turkish population, a complete coding region of the /"cystic fibrosis transmembrane conductance regulator"/ (/"CFTR"/) gene including exon-intron boundaries, on 122 unrelated /"CF"/ chromosomes from 73 Turkish /"CF"/ families was analysed by denaturing gradient gel electrophoresis and multiplex heteroduplex analysis on MDE gel matrix. In addition to 15 previously reported mutations and 12 polymorphisms, three novel mutations, namely 3172delAC, P1013L and M1028I, were detected. DeltaF508 was found to be present on 18.8% of /"CF"/ chromosomes. The second most common mutation was 1677delTA, with a frequency of 7.3%, followed by G542X and 2183AA-->G mutations, with frequencies of 4.9%. These four most common mutations in Turkish /"CF"/ population account for approximately 36% of mutations. This study could only detect 52.5% of disease-causing mutations in this population; 47.5% of /"CF"/ alleles remain to be identified, reflecting the high molecular heterogeneity of the Turkish population. | [
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9535411 | Gender-specific association of M235T polymorphism in angiotensinogen gene and diabetic nephropathy in NIDDM. | This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of nephropathy and > or = 10 years of NIDDM (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women. | Gender-specific association of M235T polymorphism in /"angiotensinogen"/ gene and diabetic nephropathy in /"NIDDM"/. | This study examined the association between the development of nephropathy in /"non-insulin-dependent diabetes mellitus"/ (/"NIDDM"/) patients and M235T polymorphism in the /"angiotensinogen"/ gene. White /"NIDDM"/ patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of nephropathy and > or = 10 years of /"NIDDM"/ (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the /"angiotensinogen"/ locus. For the /"angiotensinogen"/ gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the /"angiotensinogen"/ gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in /"NIDDM"/ men but not in women. | [
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9535411 | Gender-specific association of M235T polymorphism in angiotensinogen gene and diabetic nephropathy in NIDDM. | This study examined the association between the development of nephropathy in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the angiotensinogen gene. White NIDDM patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of nephropathy and > or = 10 years of NIDDM (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the angiotensinogen locus. For the angiotensinogen gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with nephropathy than in control subjects without this complication. This difference, expressed as the odds ratio for nephropathy among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the angiotensinogen gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women. | Gender-specific association of M235T polymorphism in /"angiotensinogen"/ gene and diabetic nephropathy in NIDDM. | This study examined the association between the development of /"nephropathy"/ in non-insulin-dependent diabetes mellitus (NIDDM) patients and M235T polymorphism in the /"angiotensinogen"/ gene. White NIDDM patients with diabetic nephropathy (case subjects, n = 117) and patients without any evidence of /"nephropathy"/ and > or = 10 years of NIDDM (control subjects, n = 125) were selected from among patients of the Joslin Diabetes Center and examined. In addition to a standardized examination, blood was drawn for DNA and determination of M235T genotypes at the /"angiotensinogen"/ locus. For the /"angiotensinogen"/ gene, the frequency of the genotype 235T/235T, known to be associated with essential hypertension, was higher among case subjects with /"nephropathy"/ than in control subjects without this complication. This difference, expressed as the odds ratio for /"nephropathy"/ among 235T/235T homozygotes in comparison with all other genotypes, was 2.2 (95% confidence interval, 1.1 to 4.4). The difference, however, was confined to men (odds ratio, 4.8; 95% confidence interval, 1.5 to 14.9), with the distribution of genotypes in case and control subjects being equal among women (odds ratio, 1.1). DNA polymorphism M235T in the /"angiotensinogen"/ gene, which is associated with higher expression of this gene, contributes to the risk of diabetic nephropathy in NIDDM men but not in women. | [
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"text_name": "nephropathy"
} | No |
9535412 | Angiotensin-converting enzyme gene polymorphism is associated with endothelium-dependent vasodilation in never treated hypertensive patients. | The response of the forearm vasculature to acetylcholine (7.5, 15, and 30 microg/min, each for 5 minutes) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min, each for 5 minutes) was evaluated in 32 never-treated hypertensive outpatients (17 men and 15 women, aged 43+/-7 years) and in 24 normotensive control subjects (14 men and 10 women, aged 42+/-6 years). Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. In both hypertensive and normotensive groups, a deletion (D)/insertion (I) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene was determined by polymerase chain reaction. The response to acetylcholine was significantly reduced in hypertensive patients versus control subjects: at the highest dose (30 microg/min), forearm blood flow was 13.9+/-6.3 mL x 100 mL tissue(-1) x min(-1) in hypertensives versus 27.1+/-9.7 mL x 100 mL tissue(-1) x min(-1) in the controls (P<.001); similarly, vascular resistance was 10.6+/-5.6 U in hypertensive patients and 4.9+/-1.9 U in normotensive subjects. In the hypertensive group, the patients with DD genotype showed significantly less endothelium-dependent vasodilation compared with ID+II genotypes (at the highest dose of acetylcholine, forearm blood flow was 12.1+/-4.2 versus 17.0+/-4.1 mL x 100 mL tissue(-1) x min(-1)) (P<.005). The vasodilator effect of sodium nitroprusside infusions was not statistically different in DD and ID+II hypertensive patients. In conclusion, our data suggest that ACE polymorphism affects endothelium-dependent vasodilation in hypertensive patients and confirm that hypertensive patients had a blunted response to the endothelium-dependent agent acetylcholine. | /"Angiotensin-converting enzyme"/ gene polymorphism is associated with endothelium-dependent vasodilation in never treated /"hypertensive"/ patients. | The response of the forearm vasculature to acetylcholine (7.5, 15, and 30 microg/min, each for 5 minutes) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min, each for 5 minutes) was evaluated in 32 never-treated /"hypertensive"/ outpatients (17 men and 15 women, aged 43+/-7 years) and in 24 normotensive control subjects (14 men and 10 women, aged 42+/-6 years). Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. In both /"hypertensive"/ and normotensive groups, a deletion (D)/insertion (I) polymorphism in intron 16 of the /"angiotensin-converting enzyme"/ (/"ACE"/) gene was determined by polymerase chain reaction. The response to acetylcholine was significantly reduced in /"hypertensive"/ patients versus control subjects: at the highest dose (30 microg/min), forearm blood flow was 13.9+/-6.3 mL x 100 mL tissue(-1) x min(-1) in /"hypertensives"/ versus 27.1+/-9.7 mL x 100 mL tissue(-1) x min(-1) in the controls (P<.001); similarly, vascular resistance was 10.6+/-5.6 U in /"hypertensive"/ patients and 4.9+/-1.9 U in normotensive subjects. In the /"hypertensive"/ group, the patients with DD genotype showed significantly less endothelium-dependent vasodilation compared with ID+II genotypes (at the highest dose of acetylcholine, forearm blood flow was 12.1+/-4.2 versus 17.0+/-4.1 mL x 100 mL tissue(-1) x min(-1)) (P<.005). The vasodilator effect of sodium nitroprusside infusions was not statistically different in DD and ID+II /"hypertensive"/ patients. In conclusion, our data suggest that /"ACE"/ polymorphism affects endothelium-dependent vasodilation in /"hypertensive"/ patients and confirm that /"hypertensive"/ patients had a blunted response to the endothelium-dependent agent acetylcholine. | [
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9535412 | Angiotensin-converting enzyme gene polymorphism is associated with endothelium-dependent vasodilation in never treated hypertensive patients. | The response of the forearm vasculature to acetylcholine (7.5, 15, and 30 microg/min, each for 5 minutes) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min, each for 5 minutes) was evaluated in 32 never-treated hypertensive outpatients (17 men and 15 women, aged 43+/-7 years) and in 24 normotensive control subjects (14 men and 10 women, aged 42+/-6 years). Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. In both hypertensive and normotensive groups, a deletion (D)/insertion (I) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene was determined by polymerase chain reaction. The response to acetylcholine was significantly reduced in hypertensive patients versus control subjects: at the highest dose (30 microg/min), forearm blood flow was 13.9+/-6.3 mL x 100 mL tissue(-1) x min(-1) in hypertensives versus 27.1+/-9.7 mL x 100 mL tissue(-1) x min(-1) in the controls (P<.001); similarly, vascular resistance was 10.6+/-5.6 U in hypertensive patients and 4.9+/-1.9 U in normotensive subjects. In the hypertensive group, the patients with DD genotype showed significantly less endothelium-dependent vasodilation compared with ID+II genotypes (at the highest dose of acetylcholine, forearm blood flow was 12.1+/-4.2 versus 17.0+/-4.1 mL x 100 mL tissue(-1) x min(-1)) (P<.005). The vasodilator effect of sodium nitroprusside infusions was not statistically different in DD and ID+II hypertensive patients. In conclusion, our data suggest that ACE polymorphism affects endothelium-dependent vasodilation in hypertensive patients and confirm that hypertensive patients had a blunted response to the endothelium-dependent agent acetylcholine. | Angiotensin-converting enzyme gene polymorphism is associated with endothelium-dependent vasodilation in never treated /"hypertensive"/ patients. | The response of the forearm vasculature to acetylcholine (7.5, 15, and 30 microg/min, each for 5 minutes) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min, each for 5 minutes) was evaluated in 32 never-treated /"hypertensive"/ outpatients (17 men and 15 women, aged 43+/-7 years) and in 24 normotensive control subjects (14 men and 10 women, aged 42+/-6 years). Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. In both /"hypertensive"/ and normotensive groups, a deletion (D)/insertion (I) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene was determined by polymerase chain reaction. The response to acetylcholine was significantly reduced in /"hypertensive"/ patients versus control subjects: at the highest dose (30 microg/min), forearm blood flow was 13.9+/-6.3 mL x 100 mL tissue(-1) x /"min(-1"/) in /"hypertensives"/ versus 27.1+/-9.7 mL x 100 mL tissue(-1) x /"min(-1"/) in the controls (P<.001); similarly, vascular resistance was 10.6+/-5.6 U in /"hypertensive"/ patients and 4.9+/-1.9 U in normotensive subjects. In the /"hypertensive"/ group, the patients with DD genotype showed significantly less endothelium-dependent vasodilation compared with ID+II genotypes (at the highest dose of acetylcholine, forearm blood flow was 12.1+/-4.2 versus 17.0+/-4.1 mL x 100 mL tissue(-1) x /"min(-1"/)) (P<.005). The vasodilator effect of sodium nitroprusside infusions was not statistically different in DD and ID+II /"hypertensive"/ patients. In conclusion, our data suggest that ACE polymorphism affects endothelium-dependent vasodilation in /"hypertensive"/ patients and confirm that /"hypertensive"/ patients had a blunted response to the endothelium-dependent agent acetylcholine. | [
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} | No |
9545398 | Mutations in btk in patients with presumed X-linked agammaglobulinemia. | In 1993, two groups showed that X-linked agammaglobulinemia (XLA) was due to mutations in a tyrosine kinase now called Btk. Most laboratories have been able to detect mutations in Btk in 80%-90% of males with presumed XLA. The remaining patients may have mutations in Btk that are difficult to identify, or they may have defects that are phenotypically similar to XLA but genotypically different. We analyzed 101 families in which affected males were diagnosed as having XLA. Mutations in Btk were identified in 38 of 40 families with more than one affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of XLA could not be confirmed by immunofluorescence studies, mutations in Btk were identified in 43 of 46 patients with presumed sporadic XLA. Two of the three remaining patients had defects in other genes required for normal B cell development, and the third patient was unlikely to have XLA, on the basis of results of extensive Btk analysis. Our techniques were unable to identify a mutation in Btk in one male with both a family history and laboratory findings suggestive of XLA. DNA samples from 41 of 49 of the mothers of males with sporadic disease and proven mutations in Btk were positive for the mutation found in their son. In the other 8 families, the mutation appeared to arise in the maternal germ line. In 20 families, haplotype analysis showed that the new mutation originated in the maternal grandfather or great-grandfather. These studies indicate that 90%-95% of males with presumed XLA have mutations in Btk. The other patients are likely to have defects in other genes. | Mutations in /"btk"/ in patients with presumed /"X-linked agammaglobulinemia"/. | In 1993, two groups showed that /"X-linked agammaglobulinemia"/ (/"XLA"/) was due to mutations in a tyrosine kinase now called /"Btk"/. Most laboratories have been able to detect mutations in /"Btk"/ in 80%-90% of males with presumed /"XLA"/LA"/. The remaining patients may have mutations in /"Btk"/ that are difficult to identify, or they may have defects that are phenotypically similar to /"XLA"/LA"/ but genotypically different. We analyzed 101 families in which affected males were diagnosed as having /"XLA"/LA"/. Mutations in /"Btk"/ were identified in 38 of 40 families with more than one affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of /"XLA"/LA"/ could not be confirmed by immunofluorescence studies, mutations in /"Btk"/ were identified in 43 of 46 patients with presumed /"sporadic XLA"/LA"/. Two of the three remaining patients had defects in other genes required for normal B cell development, and the third patient was unlikely to have /"XLA"/LA"/, on the basis of results of extensive /"Btk"/ analysis. Our techniques were unable to identify a mutation in /"Btk"/ in one male with both a family history and laboratory findings suggestive of /"XLA"/LA"/. DNA samples from 41 of 49 of the mothers of males with sporadic disease and proven mutations in /"Btk"/ were positive for the mutation found in their son. In the other 8 families, the mutation appeared to arise in the maternal germ line. In 20 families, haplotype analysis showed that the new mutation originated in the maternal grandfather or great-grandfather. These studies indicate that 90%-95% of males with presumed /"XLA"/LA"/ have mutations in /"Btk"/. The other patients are likely to have defects in other genes. | [
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} | Yes |
9545398 | Mutations in btk in patients with presumed X-linked agammaglobulinemia. | In 1993, two groups showed that X-linked agammaglobulinemia (XLA) was due to mutations in a tyrosine kinase now called Btk. Most laboratories have been able to detect mutations in Btk in 80%-90% of males with presumed XLA. The remaining patients may have mutations in Btk that are difficult to identify, or they may have defects that are phenotypically similar to XLA but genotypically different. We analyzed 101 families in which affected males were diagnosed as having XLA. Mutations in Btk were identified in 38 of 40 families with more than one affected family member and in 56 of 61 families with sporadic disease. Excluding the patients in whom the marked decrease in B cell numbers characteristic of XLA could not be confirmed by immunofluorescence studies, mutations in Btk were identified in 43 of 46 patients with presumed sporadic XLA. Two of the three remaining patients had defects in other genes required for normal B cell development, and the third patient was unlikely to have XLA, on the basis of results of extensive Btk analysis. Our techniques were unable to identify a mutation in Btk in one male with both a family history and laboratory findings suggestive of XLA. DNA samples from 41 of 49 of the mothers of males with sporadic disease and proven mutations in Btk were positive for the mutation found in their son. In the other 8 families, the mutation appeared to arise in the maternal germ line. In 20 families, haplotype analysis showed that the new mutation originated in the maternal grandfather or great-grandfather. These studies indicate that 90%-95% of males with presumed XLA have mutations in Btk. The other patients are likely to have defects in other genes. | Mutations in /"btk"/ in patients with presumed X-linked agammaglobulinemia. | In 1993, two groups showed that X-linked agammaglobulinemia (XLA) was due to mutations in a tyrosine kinase now called /"Btk"/. Most laboratories have been able to detect mutations in /"Btk"/ in 80%-90% of males with presumed /"XLA"/. The remaining patients may have mutations in /"Btk"/ that are difficult to identify, or they may have defects that are phenotypically similar to /"XLA"/ but genotypically different. We analyzed 101 families in which affected males were diagnosed as having /"XLA"/. Mutations in /"Btk"/ were identified in 38 of 40 families with more than one affected family member and in 56 of 61 families with /"sporadic disease"/. Excluding the patients in whom the marked decrease in B cell numbers characteristic of /"XLA"/ could not be confirmed by immunofluorescence studies, mutations in /"Btk"/ were identified in 43 of 46 patients with presumed sporadic /"XLA"/. Two of the three remaining patients had defects in other genes required for normal B cell development, and the third patient was unlikely to have /"XLA"/, on the basis of results of extensive /"Btk"/ analysis. Our techniques were unable to identify a mutation in /"Btk"/ in one male with both a family history and laboratory findings suggestive of /"XLA"/. DNA samples from 41 of 49 of the mothers of males with /"sporadic disease"/ and proven mutations in /"Btk"/ were positive for the mutation found in their son. In the other 8 families, the mutation appeared to arise in the maternal germ line. In 20 families, haplotype analysis showed that the new mutation originated in the maternal grandfather or great-grandfather. These studies indicate that 90%-95% of males with presumed /"XLA"/ have mutations in /"Btk"/. The other patients are likely to have defects in other genes. | [
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9550468 | Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus. | OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE. | Synergistic effect between IL-10 and /"bcl-2"/ genotypes in determining susceptibility to /"systemic lupus erythematosus"/. | OBJECTIVE: To determine whether genes participating in programmed cell death, including /"bcl-2"/, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to /"systemic lupus erythematosus"/ (/"SLE"/). METHODS: First, intragenic markers for the /"bcl-2"/, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American /"SLE"/ cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The /"bcl-2"/, Fas-L, and IL-10 loci showed significantly different allelic distribution in /"SLE"/ patients compared with controls, indicating an association between these genes and /"SLE"/. No association was found between /"SLE"/ and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the /"bcl-2"/ and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in /"SLE"/ risk, while the occurrence of these alleles together increased the odds of developing /"SLE"/ by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both /"bcl-2"/ and IL-10 are at significant risk of developing /"SLE"/. | [
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"text_name": "systemic lupus erythematosus"
} | Yes |
9550468 | Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus. | OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE. | Synergistic effect between /"IL-10"/ and bcl-2 genotypes in determining susceptibility to /"systemic lupus erythematosus"/. | OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, /"IL-10"/, Fas-L, and CTLA-4, may contribute to the genetic predisposition to /"systemic lupus erythematosus"/ (/"SLE"/). METHODS: First, intragenic markers for the bcl-2, /"IL-10"/, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American /"SLE"/ cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and /"IL-10"/ loci showed significantly different allelic distribution in /"SLE"/ patients compared with controls, indicating an association between these genes and /"SLE"/. No association was found between /"SLE"/ and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and /"IL-10"/ genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in /"SLE"/ risk, while the occurrence of these alleles together increased the odds of developing /"SLE"/ by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and /"IL-10"/ are at significant risk of developing /"SLE"/. | [
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9550468 | Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus. | OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE. | Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to /"systemic lupus erythematosus"/. | OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and /"CTLA-4"/, may contribute to the genetic predisposition to /"systemic lupus erythematosus"/ (/"SLE"/). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and /"CTLA-4"/ genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American /"SLE"/ cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in /"SLE"/ patients compared with controls, indicating an association between these genes and /"SLE"/. No association was found between /"SLE"/ and the /"CTLA-4"/ gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in /"SLE"/ risk, while the occurrence of these alleles together increased the odds of developing /"SLE"/ by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing /"SLE"/. | [
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} | No |
9550468 | Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus. | OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE. | Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to /"systemic lupus erythematosus"/. | OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and /"CTLA-4"/, may contribute to the genetic predisposition to /"systemic lupus erythematosus"/ (/"SLE"/). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and /"CTLA-4"/ genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American /"SLE"/ cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in /"SLE"/ patients compared with controls, indicating an association between these genes and /"SLE"/. No association was found between /"SLE"/ and the /"CTLA-4"/ gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in /"SLE"/ risk, while the occurrence of these alleles together increased the odds of developing /"SLE"/ by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing /"SLE"/. | [
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9554754 | A new missense substitution at a mutational hot spot of the androgen receptor in siblings with complete androgen insensitivity syndrome. | Several mutations have been described in the human androgen receptor gene including constitutional mutations in androgen insensitivity syndrome, somatic mutations in prostate cancer and triplet expansions in Kennedy's disease (Gottlieb et al. 1997). Here we report on two siblings with complete androgen insensitivity and a novel missense mutation, D695V, in their androgen receptor gene. The two XY females are siblings of German descent and presented at the ages of 23 and 19 years, respectively, with typical clinical features of complete androgen insensitivity. We found both siblings to be hemizygous for a new adenine to thymine transversion at the second nucleotide of codon 695 within the fourth exon of the human androgen receptor gene. The resulting missense mutation D695V is located at the amino-terminal border of the ligand-binding domain of the androgen receptor. The aspartic acid residue at this position is highly conserved in the steroid binding domains of other members of the nuclear receptor family and has already been found to be the site of two other missense mutations associated with androgen insensitivity syndrome (Ris Stalpers et al. 1991, Hiort et al. 1996). Three of four reported subjects showed the complete androgen insensitivity phenotype, in accordance with the two siblings in our study. We suggest that the existence of three pathological amino acid substitutions for aspartic acid 695 most likely reflects the essential role of this residue for normal androgen receptor function in male sexual differentiation. | A new missense substitution at a mutational hot spot of the /"androgen receptor"/ in siblings with /"complete androgen insensitivity syndrome"/. | Several mutations have been described in the human /"androgen receptor"/ gene including constitutional mutations in /"androgen insensitivity syndrome"/, somatic mutations in prostate cancer and triplet expansions in Kennedy's disease (Gottlieb et al. 1997). Here we report on two siblings with /"complete androgen insensitivity"/ and a novel missense mutation, D695V, in their /"androgen receptor"/ gene. The two XY females are siblings of German descent and presented at the ages of 23 and 19 years, respectively, with typical clinical features of /"complete androgen insensitivity"/. We found both siblings to be hemizygous for a new adenine to thymine transversion at the second nucleotide of codon 695 within the fourth exon of the human /"androgen receptor"/ gene. The resulting missense mutation D695V is located at the amino-terminal border of the ligand-binding domain of the /"androgen receptor"/. The aspartic acid residue at this position is highly conserved in the steroid binding domains of other members of the nuclear receptor family and has already been found to be the site of two other missense mutations associated with /"androgen insensitivity syndrome"/ (Ris Stalpers et al. 1991, Hiort et al. 1996). Three of four reported subjects showed the /"complete androgen insensitivity"/ phenotype, in accordance with the two siblings in our study. We suggest that the existence of three pathological amino acid substitutions for aspartic acid 695 most likely reflects the essential role of this residue for normal /"androgen receptor"/ function in male sexual differentiation. | [
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} | Yes |
9554754 | A new missense substitution at a mutational hot spot of the androgen receptor in siblings with complete androgen insensitivity syndrome. | Several mutations have been described in the human androgen receptor gene including constitutional mutations in androgen insensitivity syndrome, somatic mutations in prostate cancer and triplet expansions in Kennedy's disease (Gottlieb et al. 1997). Here we report on two siblings with complete androgen insensitivity and a novel missense mutation, D695V, in their androgen receptor gene. The two XY females are siblings of German descent and presented at the ages of 23 and 19 years, respectively, with typical clinical features of complete androgen insensitivity. We found both siblings to be hemizygous for a new adenine to thymine transversion at the second nucleotide of codon 695 within the fourth exon of the human androgen receptor gene. The resulting missense mutation D695V is located at the amino-terminal border of the ligand-binding domain of the androgen receptor. The aspartic acid residue at this position is highly conserved in the steroid binding domains of other members of the nuclear receptor family and has already been found to be the site of two other missense mutations associated with androgen insensitivity syndrome (Ris Stalpers et al. 1991, Hiort et al. 1996). Three of four reported subjects showed the complete androgen insensitivity phenotype, in accordance with the two siblings in our study. We suggest that the existence of three pathological amino acid substitutions for aspartic acid 695 most likely reflects the essential role of this residue for normal androgen receptor function in male sexual differentiation. | A new missense substitution at a mutational hot spot of the /"androgen receptor"/ in siblings with complete androgen insensitivity syndrome. | Several mutations have been described in the human /"androgen receptor"/ gene including constitutional mutations in androgen insensitivity syndrome, somatic mutations in /"prostate cancer"/ and triplet expansions in Kennedy's disease (Gottlieb et al. 1997). Here we report on two siblings with complete androgen insensitivity and a novel missense mutation, D695V, in their /"androgen receptor"/ gene. The two XY females are siblings of German descent and presented at the ages of 23 and 19 years, respectively, with typical clinical features of complete androgen insensitivity. We found both siblings to be hemizygous for a new adenine to thymine transversion at the second nucleotide of codon 695 within the fourth exon of the human /"androgen receptor"/ gene. The resulting missense mutation D695V is located at the amino-terminal border of the ligand-binding domain of the /"androgen receptor"/. The aspartic acid residue at this position is highly conserved in the steroid binding domains of other members of the nuclear receptor family and has already been found to be the site of two other missense mutations associated with androgen insensitivity syndrome (Ris Stalpers et al. 1991, Hiort et al. 1996). Three of four reported subjects showed the complete androgen insensitivity phenotype, in accordance with the two siblings in our study. We suggest that the existence of three pathological amino acid substitutions for aspartic acid 695 most likely reflects the essential role of this residue for normal /"androgen receptor"/ function in male sexual differentiation. | [
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} | {
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"entity_id": "D011471",
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"text_name": "prostate cancer"
} | No |
9620294 | Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. | Mutations in PATCHED (PTC), the human homolog of the Drosophila patched gene, have been identified in most exons of the gene in patients with the basal cell nevus syndrome and in sporadic basal cell carcinomas. We have screened the 23 PTC exons for mutations using single strand conformation polymorphism analysis of DNA from 86 basal cell nevus syndrome probands, 26 sporadic basal cell carcinomas, and seven basal cell nevus syndrome-associated basal cell carcinomas. This screen identified mutations located in eight exons in 13 of the basal cell nevus syndrome patients and in three of the tumors. The most common mutations were frameshifts resulting in premature chain termination. These results provide further evidence for the crucial role of PTC as a tumor suppressor in human keratinocytes. | Identification of mutations in the human /"PATCHED"/ gene in sporadic basal cell carcinomas and in patients with the /"basal cell nevus syndrome"/. | Mutations in /"PATCHED"/ (PTC), the human homolog of the Drosophila /"patched"/ gene, have been identified in most exons of the gene in patients with the /"basal cell nevus syndrome"/ and in sporadic basal cell carcinomas. We have screened the 23 PTC exons for mutations using single strand conformation polymorphism analysis of DNA from 86 /"basal cell nevus syndrome"/ probands, 26 sporadic basal cell carcinomas, and seven /"basal cell nevus syndrome"/-associated basal cell carcinomas. This screen identified mutations located in eight exons in 13 of the /"basal cell nevus syndrome"/ patients and in three of the tumors. The most common mutations were frameshifts resulting in premature chain termination. These results provide further evidence for the crucial role of PTC as a tumor suppressor in human keratinocytes. | [
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} | {
"begin_idx": "113",
"end_idx": "138",
"entity_id": "D001478",
"entity_type": "Disease",
"text_name": "basal cell nevus syndrome"
} | Yes |
9620294 | Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. | Mutations in PATCHED (PTC), the human homolog of the Drosophila patched gene, have been identified in most exons of the gene in patients with the basal cell nevus syndrome and in sporadic basal cell carcinomas. We have screened the 23 PTC exons for mutations using single strand conformation polymorphism analysis of DNA from 86 basal cell nevus syndrome probands, 26 sporadic basal cell carcinomas, and seven basal cell nevus syndrome-associated basal cell carcinomas. This screen identified mutations located in eight exons in 13 of the basal cell nevus syndrome patients and in three of the tumors. The most common mutations were frameshifts resulting in premature chain termination. These results provide further evidence for the crucial role of PTC as a tumor suppressor in human keratinocytes. | Identification of mutations in the human /"PATCHED"/ gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. | Mutations in /"PATCHED"/ (PTC), the human homolog of the Drosophila /"patched"/ gene, have been identified in most exons of the gene in patients with the basal cell nevus syndrome and in sporadic basal cell carcinomas. We have screened the 23 PTC exons for mutations using single strand conformation polymorphism analysis of DNA from 86 basal cell nevus syndrome probands, 26 sporadic basal cell carcinomas, and seven basal cell nevus syndrome-associated /"basal cell carcinomas"/. This screen identified mutations located in eight exons in 13 of the basal cell nevus syndrome patients and in three of the tumors. The most common mutations were frameshifts resulting in premature chain termination. These results provide further evidence for the crucial role of PTC as a tumor suppressor in human keratinocytes. | [
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] | {
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} | {
"begin_idx": "587",
"end_idx": "608",
"entity_id": "D002280",
"entity_type": "Disease",
"text_name": "basal cell carcinomas"
} | No |
9714430 | Ile225Thr loop mutation in the lipoprotein lipase (LPL) gene is a de novo event. | Mutations in the lipoprotein lipase (LPL) gene are the most important cause of familial chylomicronemia with over 70 mutations being recorded to date. Thus far de novo mutations have not been described. Here we report on the molecular analysis of the family of a patient previously reported to be LPL deficient on the basis of compound heterozygosity for the Arg243His and Ile225Thr mutations, the latter being the first and only mutation identified in the loop region of LPL. Both parents of the propositus were screened for the presence of these two mutations to confirm their status as obligate heterozygotes and to determine the mutation allocation. Although paternal inheritance of the Arg243His allele could be established, maternal DNA did not show carrier status for the Ile225Thr substitution. An examination of maternity, using LPL restriction fragment length polymorphisms four polymorphic CA repeats and ApoE genotypes, was consistent with correct biological parentage for the propositus. Therefore, we conclude that the Ile225Thr mutation constitutes a de novo event, the first to be reported in the LPL gene. | Ile225Thr loop mutation in the /"lipoprotein lipase"/ (/"LPL"/) gene is a de novo event. | Mutations in the /"lipoprotein lipase"/ (/"LPL"/) gene are the most important cause of /"familial chylomicronemia"/ with over 70 mutations being recorded to date. Thus far de novo mutations have not been described. Here we report on the molecular analysis of the family of a patient previously reported to be /"LPL"/ deficient on the basis of compound heterozygosity for the Arg243His and Ile225Thr mutations, the latter being the first and only mutation identified in the loop region of /"LPL"/. Both parents of the propositus were screened for the presence of these two mutations to confirm their status as obligate heterozygotes and to determine the mutation allocation. Although paternal inheritance of the Arg243His allele could be established, maternal DNA did not show carrier status for the Ile225Thr substitution. An examination of maternity, using /"LPL"/ restriction fragment length polymorphisms four polymorphic CA repeats and ApoE genotypes, was consistent with correct biological parentage for the propositus. Therefore, we conclude that the Ile225Thr mutation constitutes a de novo event, the first to be reported in the /"LPL"/ gene. | [
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"entity_type": "Disease",
"text_name": "familial chylomicronemia"
} | Yes |
9714430 | Ile225Thr loop mutation in the lipoprotein lipase (LPL) gene is a de novo event. | Mutations in the lipoprotein lipase (LPL) gene are the most important cause of familial chylomicronemia with over 70 mutations being recorded to date. Thus far de novo mutations have not been described. Here we report on the molecular analysis of the family of a patient previously reported to be LPL deficient on the basis of compound heterozygosity for the Arg243His and Ile225Thr mutations, the latter being the first and only mutation identified in the loop region of LPL. Both parents of the propositus were screened for the presence of these two mutations to confirm their status as obligate heterozygotes and to determine the mutation allocation. Although paternal inheritance of the Arg243His allele could be established, maternal DNA did not show carrier status for the Ile225Thr substitution. An examination of maternity, using LPL restriction fragment length polymorphisms four polymorphic CA repeats and ApoE genotypes, was consistent with correct biological parentage for the propositus. Therefore, we conclude that the Ile225Thr mutation constitutes a de novo event, the first to be reported in the LPL gene. | Ile225Thr loop mutation in the lipoprotein lipase (LPL) gene is a de novo event. | Mutations in the lipoprotein lipase (LPL) gene are the most important cause of /"familial chylomicronemia"/ with over 70 mutations being recorded to date. Thus far de novo mutations have not been described. Here we report on the molecular analysis of the family of a patient previously reported to be LPL deficient on the basis of compound heterozygosity for the Arg243His and Ile225Thr mutations, the latter being the first and only mutation identified in the loop region of LPL. Both parents of the propositus were screened for the presence of these two mutations to confirm their status as obligate heterozygotes and to determine the mutation allocation. Although paternal inheritance of the Arg243His allele could be established, maternal DNA did not show carrier status for the Ile225Thr substitution. An examination of maternity, using LPL restriction fragment length polymorphisms four polymorphic CA repeats and /"ApoE"/ genotypes, was consistent with correct biological parentage for the propositus. Therefore, we conclude that the Ile225Thr mutation constitutes a de novo event, the first to be reported in the LPL gene. | [
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] | {
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} | {
"begin_idx": "160",
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"entity_id": "D008072",
"entity_type": "Disease",
"text_name": "familial chylomicronemia"
} | No |
9747038 | Connatal Pelizaeus-Merzbacher disease: a missense mutation in exon 4 of the proteolipid protein (PLP) gene. | We investigated the proteolipid protein (PLP) gene in two brothers in a Japanese family with a connatal form of Pelizaeus-Merzbacher disease (PMD). Direct sequencing of the PLP gene revealed an A-to-T transition in exon 4, which led to an Asp-to-Val substitution at residue 202. Their mother was confirmed to be heterozygous for the mutation. The mutation was not found in 78 X-chromosomes of normal Japanese individuals. A correlation between the clinical severity of the disease in the brothers and the Asp202-to-Val mutation in the PLP gene was suggested. | Connatal /"Pelizaeus-Merzbacher disease"/: a missense mutation in exon 4 of the /"proteolipid protein"/ (/"PLP"/) gene. | We investigated the /"proteolipid protein"/ (/"PLP"/) gene in two brothers in a Japanese family with a connatal form of /"Pelizaeus-Merzbacher disease"/ (/"PMD"/). Direct sequencing of the /"PLP"/ gene revealed an A-to-T transition in exon 4, which led to an Asp-to-Val substitution at residue 202. Their mother was confirmed to be heterozygous for the mutation. The mutation was not found in 78 X-chromosomes of normal Japanese individuals. A correlation between the clinical severity of the disease in the brothers and the Asp202-to-Val mutation in the /"PLP"/ gene was suggested. | [
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9759613 | The molecular basis of antithrombin deficiency in Belgian and Dutch families. | The molecular basis of hereditary antithrombin (AT) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed. DNA studies of the AT gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intron-exon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the AT gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect. | The molecular basis of /"antithrombin"/in"/ deficiency in Belgian and Dutch families. | The molecular basis of hereditary /"antithrombin"/in"/ (/"AT"/AT"/) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I /"AT deficiency"/, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed. DNA studies of the /"AT"/AT"/ gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intron-exon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of /"AT deficiency"/. In these cases, Southern blot and polymorphism analysis of different parts of the /"AT"/AT"/ gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect. | [
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9759613 | The molecular basis of antithrombin deficiency in Belgian and Dutch families. | The molecular basis of hereditary antithrombin (AT) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed. DNA studies of the AT gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intron-exon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the AT gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect. | The molecular basis of /"antithrombin"/ deficiency in Belgian and Dutch families. | The molecular basis of hereditary /"antithrombin"/ (/"AT"/) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed. DNA studies of the /"AT"/ gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intron-exon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying /"genetic defect"/ was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the /"AT"/ gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the /"genetic defect"/. | [
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9823305 | Association of cytochrome P450 1B1 (CYP1B1) polymorphism with steroid receptor status in breast cancer. | A key enzyme involved in the production of potentially carcinogenic estrogen metabolites and the activation of environmental carcinogens is cytochrome P450 1B1 (CYP1B1), the predominant member of the CYP1 family expressed in normal breast tissue and breast cancer. Because of the preeminent role of CYP1B1 in mammary estrogen/carcinogen metabolism, we examined the CYP1B1 gene to determine whether genetic differences could account for interindividual differences in breast cancer risk. We focused on exon 3, because it encodes the catalytically important heme binding domain of the enzyme, and discovered three polymorphisms of which two are associated with amino acid substitutions in codons 432 (Val-->Leu) and 453 (Asn-->Ser), designated as m1 and m2, respectively. Approximately 40% of Caucasian women have the m1 Val allele compared with nearly 70% of African-American women (P < 0.0001). The allele frequency also differs significantly in m2, with the rare Ser allele being present in 17.4% of Caucasians but only in 3.4% of African Americans (P < 0.0003). To determine whether the polymorphic CYP1B1 alleles hold implications as potential breast cancer risk factors, we compared the CYP1B1 genotypes in 164 Caucasian and 59 African-American breast cancer cases with those in age-, race-, and frequency-matched controls. Odds ratio calculations failed to show a significant association between any of the genotypes and breast cancer. Because CYP1B1 is known to be involved in mammary estrogen metabolism, we investigated whether the estrogen receptor status is influenced by the CYP1B1 genotypes. Caucasian patients with the m1 Val/Val genotype have a significantly higher percentage of estrogen receptor-positive (P = 0.02) and progesterone receptor-positive breast cancers (P = 0.003). There was no correlation with the m2 genotypes. These data suggest that the CYP1B1 polymorphisms in exon 3 are not associated with increased breast cancer risk but that the m1 polymorphism may be functionally important for steroid receptor expression in breast cancer of Caucasian patients. | Association of /"cytochrome P450 1B1"/ (/"CYP1B1"/) polymorphism with steroid receptor status in /"breast cancer"/. | A key enzyme involved in the production of potentially carcinogenic estrogen metabolites and the activation of environmental carcinogens is /"cytochrome P450 1B1"/ (/"CYP1B1"/), the predominant member of the CYP1 family expressed in normal breast tissue and /"breast cancer"/. Because of the preeminent role of /"CYP1B1"/ in mammary estrogen/carcinogen metabolism, we examined the /"CYP1B1"/ gene to determine whether genetic differences could account for interindividual differences in /"breast cancer"/ risk. We focused on exon 3, because it encodes the catalytically important heme binding domain of the enzyme, and discovered three polymorphisms of which two are associated with amino acid substitutions in codons 432 (Val-->Leu) and 453 (Asn-->Ser), designated as m1 and m2, respectively. Approximately 40% of Caucasian women have the m1 Val allele compared with nearly 70% of African-American women (P < 0.0001). The allele frequency also differs significantly in m2, with the rare Ser allele being present in 17.4% of Caucasians but only in 3.4% of African Americans (P < 0.0003). To determine whether the polymorphic /"CYP1B1"/ alleles hold implications as potential /"breast cancer"/ risk factors, we compared the /"CYP1B1"/ genotypes in 164 Caucasian and 59 African-American /"breast cancer"/ cases with those in age-, race-, and frequency-matched controls. Odds ratio calculations failed to show a significant association between any of the genotypes and /"breast cancer"/. Because /"CYP1B1"/ is known to be involved in mammary estrogen metabolism, we investigated whether the estrogen receptor status is influenced by the /"CYP1B1"/ genotypes. Caucasian patients with the m1 Val/Val genotype have a significantly higher percentage of estrogen receptor-positive (P = 0.02) and progesterone receptor-positive /"breast cancers"/ (P = 0.003). There was no correlation with the m2 genotypes. These data suggest that the /"CYP1B1"/ polymorphisms in exon 3 are not associated with /"increased breast cancer"/ risk but that the m1 polymorphism may be functionally important for steroid receptor expression in /"breast cancer"/ of Caucasian patients. | [
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9823305 | Association of cytochrome P450 1B1 (CYP1B1) polymorphism with steroid receptor status in breast cancer. | A key enzyme involved in the production of potentially carcinogenic estrogen metabolites and the activation of environmental carcinogens is cytochrome P450 1B1 (CYP1B1), the predominant member of the CYP1 family expressed in normal breast tissue and breast cancer. Because of the preeminent role of CYP1B1 in mammary estrogen/carcinogen metabolism, we examined the CYP1B1 gene to determine whether genetic differences could account for interindividual differences in breast cancer risk. We focused on exon 3, because it encodes the catalytically important heme binding domain of the enzyme, and discovered three polymorphisms of which two are associated with amino acid substitutions in codons 432 (Val-->Leu) and 453 (Asn-->Ser), designated as m1 and m2, respectively. Approximately 40% of Caucasian women have the m1 Val allele compared with nearly 70% of African-American women (P < 0.0001). The allele frequency also differs significantly in m2, with the rare Ser allele being present in 17.4% of Caucasians but only in 3.4% of African Americans (P < 0.0003). To determine whether the polymorphic CYP1B1 alleles hold implications as potential breast cancer risk factors, we compared the CYP1B1 genotypes in 164 Caucasian and 59 African-American breast cancer cases with those in age-, race-, and frequency-matched controls. Odds ratio calculations failed to show a significant association between any of the genotypes and breast cancer. Because CYP1B1 is known to be involved in mammary estrogen metabolism, we investigated whether the estrogen receptor status is influenced by the CYP1B1 genotypes. Caucasian patients with the m1 Val/Val genotype have a significantly higher percentage of estrogen receptor-positive (P = 0.02) and progesterone receptor-positive breast cancers (P = 0.003). There was no correlation with the m2 genotypes. These data suggest that the CYP1B1 polymorphisms in exon 3 are not associated with increased breast cancer risk but that the m1 polymorphism may be functionally important for steroid receptor expression in breast cancer of Caucasian patients. | Association of cytochrome P450 1B1 (CYP1B1) polymorphism with steroid receptor status in /"breast cancer"/. | A key enzyme involved in the production of potentially carcinogenic estrogen metabolites and the activation of environmental carcinogens is cytochrome P450 1B1 (CYP1B1), the predominant member of the CYP1 family expressed in normal breast tissue and /"breast cancer"/. Because of the preeminent role of CYP1B1 in mammary estrogen/carcinogen metabolism, we examined the CYP1B1 gene to determine whether genetic differences could account for interindividual differences in /"breast cancer"/ risk. We focused on exon 3, because it encodes the catalytically important heme binding domain of the enzyme, and discovered three polymorphisms of which two are associated with amino acid substitutions in codons 432 (Val-->Leu) and 453 (Asn-->Ser), designated as /"m1 and m2"/, respectively. Approximately 40% of Caucasian women have the m1 Val allele compared with nearly 70% of African-American women (P < 0.0001). The allele frequency also differs significantly in m2, with the rare Ser allele being present in 17.4% of Caucasians but only in 3.4% of African Americans (P < 0.0003). To determine whether the polymorphic CYP1B1 alleles hold implications as potential /"breast cancer"/ risk factors, we compared the CYP1B1 genotypes in 164 Caucasian and 59 African-American /"breast cancer"/ cases with those in age-, race-, and frequency-matched controls. Odds ratio calculations failed to show a significant association between any of the genotypes and /"breast cancer"/. Because CYP1B1 is known to be involved in mammary estrogen metabolism, we investigated whether the estrogen receptor status is influenced by the CYP1B1 genotypes. Caucasian patients with the m1 Val/Val genotype have a significantly higher percentage of estrogen receptor-positive (P = 0.02) and progesterone receptor-positive /"breast cancers"/ (P = 0.003). There was no correlation with the m2 genotypes. These data suggest that the CYP1B1 polymorphisms in exon 3 are not associated with /"increased breast cancer"/ risk but that the m1 polymorphism may be functionally important for steroid receptor expression in /"breast cancer"/ of Caucasian patients. | [
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9845763 | [Association of VNTR region of the human serotonin transporter gene with bipolar disorder among the Han Chinese]. | OBJECTIVE: The serotonin transporter gene (SERT) plays an important role in the serotonin uptake into neurons. This paper reports a population and association study among the Han Chinese. METHODS: DNA were extracted from peripheral blood samples of 50 patients with bipolar disorder (DSM-IIIR), 170 unrelated healthy Han Chinese individuals and 10 healthy trios for polymerase chain reaction. The VNTR locus was amplified and PCR products were separated on the 2% agrose gel. RESULTS: All the three alleles(9,10 and 12 copies of repeat unit) reported in other studies were observed in this study with frequency 0.0029, 0.0676 and 0.9294, respectively. Four genotypes distributed in Caucasian: 12/12, 12/10, 12/9 and 10/10 were also found in the Han Chinese population. A significant difference in the allele frequency between the Han Chinese and Caucasian populations was found(P 0.000000001). No disequilibrium was observed after checking the Hardy-Weinberg equilibrium (P=0. 9995). The hereditary stability of this locus in accordance with the rules of Mendelian inheritance was demonstrated in the analysis of ten trios. In addition, a significant increase of frequency of the allele 10 in female patients with bipolar disorder was found (P=0. 043). CONCLUSION: The data of association study might indicate a different mechanism of aetiology of bipolar disorder in male and female. | [Association of VNTR region of the human /"serotonin transporter"/ gene with /"bipolar disorder"/ among the Han Chinese]. | OBJECTIVE: The /"serotonin transporter"/ gene (/"SERT"/) plays an important role in the serotonin uptake into neurons. This paper reports a population and association study among the Han Chinese. METHODS: DNA were extracted from peripheral blood samples of 50 patients with /"bipolar disorder"/ (DSM-IIIR), 170 unrelated healthy Han Chinese individuals and 10 healthy trios for polymerase chain reaction. The VNTR locus was amplified and PCR products were separated on the 2% agrose gel. RESULTS: All the three alleles(9,10 and 12 copies of repeat unit) reported in other studies were observed in this study with frequency 0.0029, 0.0676 and 0.9294, respectively. Four genotypes distributed in Caucasian: 12/12, 12/10, 12/9 and 10/10 were also found in the Han Chinese population. A significant difference in the allele frequency between the Han Chinese and Caucasian populations was found(P 0.000000001). No disequilibrium was observed after checking the Hardy-Weinberg equilibrium (P=0. 9995). The hereditary stability of this locus in accordance with the rules of Mendelian inheritance was demonstrated in the analysis of ten trios. In addition, a significant increase of frequency of the allele 10 in female patients with /"bipolar disorder"/ was found (P=0. 043). CONCLUSION: The data of association study might indicate a different mechanism of aetiology of /"bipolar disorder"/ in male and female. | [
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9858366 | Short CAG repeats within the hSKCa3 gene associated with schizophrenia: results of a family-based study. | In a family-based association study we investigated transmission of a multiallelic CAG repeat in a novel neuronal potassium channel gene, hSKCa3, in 59 parent/ offspring trios. In contrast to recent reports of an association of moderately large repeats with schizophrenia in case-control studies, our findings indicate that short CAG repeats (< or=19 repeats) are transmitted at an increased frequency to schizophrenic offspring (p=0.014), particularly among familial cases (p=0.007). No evidence for a parent-of-origin effect was found. Multiallelic TDT procedure showed no association of individual CAG repeats to schizophrenia. Further studies using family-based designs should clarify whether hSKCa3 is a susceptibility factor to schizophrenia or co-segregates with a major disease gene in tight linkage. | Short CAG repeats within the /"hSKCa3"/ gene associated with /"schizophrenia"/: results of a family-based study. | In a family-based association study we investigated transmission of a multiallelic CAG repeat in a novel neuronal potassium channel gene, /"hSKCa3"/, in 59 parent/ offspring trios. In contrast to recent reports of an association of moderately large repeats with /"schizophrenia"/ in case-control studies, our findings indicate that short CAG repeats (< or=19 repeats) are transmitted at an increased frequency to /"schizophrenic"/ offspring (p=0.014), particularly among familial cases (p=0.007). No evidence for a parent-of-origin effect was found. Multiallelic TDT procedure showed no association of individual CAG repeats to /"schizophrenia"/. Further studies using family-based designs should clarify whether /"hSKCa3"/ is a susceptibility factor to /"schizophrenia"/ or co-segregates with a major disease gene in tight linkage. | [
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9861562 | Intralymphatic interleukin-2 in combination with zidovudine for the therapy of patients with AIDS. | In a pilot study the safety and therapeutic effects of an immunostimulatory intralymphatic treatment with natural human interleukin-2 (IL-2) in combination with zidovudine were evaluated in nine patients with AIDS. Therapy with IL-2 consisted of one subcutaneous injection of 0.1 microgram/kg IL-2, followed by four intralymphatic IL-2 infusions of 0.1 microgram/kg each within a period of up to 15 days. Enlargement of lymph nodes was seen in six and a transient increase of CD4 cells in five out of nine persons in association with the IL-2 therapy. An increase of HIV p24-antigenemia was observed only in the two patients in whom zidovudine dosage had to be reduced because of side effects. Moderate clinical side effects occurred in eight of the nine patients. Four patients developed zidovudine associated anemia. Six participants showed a favourable course of disease with survival of 25 to 54 months (median 30 months) despite a previous diagnosis of manifest AIDS before IL-2 therapy. This pilot study demonstrates that a combination therapy with intralymphatic IL-2 and zidovudine can induce positive immunomodulatory effects, even in the presence of manifest AIDS. Further studies should explore the tolerability and effects of a prolonged therapy with IL-2 in combination with a more potent antiviral drug combination therapy. | Intralymphatic /"interleukin-2"/ in combination with zidovudine for the therapy of patients with /"AIDS"/. | In a pilot study the safety and therapeutic effects of an immunostimulatory intralymphatic treatment with natural human /"interleukin-2"/ (/"IL-2"/) in combination with zidovudine were evaluated in nine patients with /"AIDS"/. Therapy with /"IL-2"/ consisted of one subcutaneous injection of 0.1 microgram/kg /"IL-2"/, followed by four intralymphatic /"IL-2"/ infusions of 0.1 microgram/kg each within a period of up to 15 days. Enlargement of lymph nodes was seen in six and a transient increase of CD4 cells in five out of nine persons in association with the /"IL-2"/ therapy. An increase of HIV p24-antigenemia was observed only in the two patients in whom zidovudine dosage had to be reduced because of side effects. Moderate clinical side effects occurred in eight of the nine patients. Four patients developed zidovudine associated anemia. Six participants showed a favourable course of disease with survival of 25 to 54 months (median 30 months) despite a previous diagnosis of manifest /"AIDS"/ before /"IL-2"/ therapy. This pilot study demonstrates that a combination therapy with intralymphatic /"IL-2"/ and zidovudine can induce positive immunomodulatory effects, even in the presence of manifest /"AIDS"/. Further studies should explore the tolerability and effects of a prolonged therapy with /"IL-2"/ in combination with a more potent antiviral drug combination therapy. | [
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9861562 | Intralymphatic interleukin-2 in combination with zidovudine for the therapy of patients with AIDS. | In a pilot study the safety and therapeutic effects of an immunostimulatory intralymphatic treatment with natural human interleukin-2 (IL-2) in combination with zidovudine were evaluated in nine patients with AIDS. Therapy with IL-2 consisted of one subcutaneous injection of 0.1 microgram/kg IL-2, followed by four intralymphatic IL-2 infusions of 0.1 microgram/kg each within a period of up to 15 days. Enlargement of lymph nodes was seen in six and a transient increase of CD4 cells in five out of nine persons in association with the IL-2 therapy. An increase of HIV p24-antigenemia was observed only in the two patients in whom zidovudine dosage had to be reduced because of side effects. Moderate clinical side effects occurred in eight of the nine patients. Four patients developed zidovudine associated anemia. Six participants showed a favourable course of disease with survival of 25 to 54 months (median 30 months) despite a previous diagnosis of manifest AIDS before IL-2 therapy. This pilot study demonstrates that a combination therapy with intralymphatic IL-2 and zidovudine can induce positive immunomodulatory effects, even in the presence of manifest AIDS. Further studies should explore the tolerability and effects of a prolonged therapy with IL-2 in combination with a more potent antiviral drug combination therapy. | Intralymphatic /"interleukin-2"/ in combination with zidovudine for the therapy of patients with AIDS. | In a pilot study the safety and therapeutic effects of an immunostimulatory intralymphatic treatment with natural human /"interleukin-2"/ (/"IL-2"/) in combination with zidovudine were evaluated in nine patients with AIDS. Therapy with /"IL-2"/ consisted of one subcutaneous injection of 0.1 microgram/kg /"IL-2"/, followed by four intralymphatic /"IL-2"/ infusions of 0.1 microgram/kg each within a period of up to 15 days. Enlargement of lymph nodes was seen in six and a transient increase of CD4 cells in five out of nine persons in association with the /"IL-2"/ therapy. An increase of HIV p24-antigenemia was observed only in the two patients in whom zidovudine dosage had to be reduced because of side effects. Moderate clinical side effects occurred in eight of the nine patients. Four patients developed zidovudine associated /"anemia"/. Six participants showed a favourable course of disease with survival of 25 to 54 months (median 30 months) despite a previous diagnosis of manifest AIDS before /"IL-2"/ therapy. This pilot study demonstrates that a combination therapy with intralymphatic /"IL-2"/ and zidovudine can induce positive immunomodulatory effects, even in the presence of manifest AIDS. Further studies should explore the tolerability and effects of a prolonged therapy with /"IL-2"/ in combination with a more potent antiviral drug combination therapy. | [
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9865924 | A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. | NAD(P)H:quinone oxidoreductase (NQO1; DT-diaphorase) is elevated in certain tumors, such as non-small cell lung cancer (NSCLC). Compounds such as mitomycin C and streptonigrin are efficiently bioactivated by NQO1 and have been used in an enzyme-directed approach to chemotherapy. Previously, 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone (MeDZQ) was identified as a potential antitumor agent based on its high rate of bioactivation by human NQO1 and its selective cytotoxicity to cells containing elevated NQO1. RH1, a water-soluble analogue of MeDZQ synthesized in this work, was a better substrate for recombinant human NQO1 than the parent compound. RH1 was, correspondingly, more cytotoxic to human tumor cells expressing elevated NQO1 activity (H460 NSCLC and HT29 human colon carcinoma), as measured by 3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium assay, than it was to cells deficient in NQO1 activity (H596 NSCLC and BE human colon carcinoma). RH1 exhibited a greater selective toxicity (ratio of IC50s in H596:H460 and BE:HT29) to cells with elevated NQO1 activity relative to MeDZQ. Additionally, we report the establishment of a stable line of BE human colon carcinoma cells transfected with wild-type human NQO1 (BE-NQ7). BE cells are devoid of NQO1 activity due to a homozygous point mutation in the NQO1 gene. In comparison to the parental cell line, RH1, MeDZQ, and mitomycin C were significantly more cytotoxic to BE-NQ7 cells (17-, 7-, and 3-fold, respectively), confirming that the presence of NQO1 is sufficient to increase cytotoxicity of these antitumor quinones. These data suggest that RH1 may be an effective NQO1-directed antitumor agent for the therapy of tumors with elevated NQO1 activity, such as NSCLC. | A new screening system for NAD(P)H:quinone oxidoreductase (/"NQO1"/)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a /"NQO1"/-directed antitumor agent. | NAD(P)H:quinone oxidoreductase (/"NQO1"/; /"DT-diaphorase"/) is elevated in certain tumors, such as /"non-small cell lung cancer"/ (/"NSCLC"/). Compounds such as mitomycin C and streptonigrin are efficiently bioactivated by /"NQO1"/ and have been used in an enzyme-directed approach to chemotherapy. Previously, 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone (MeDZQ) was identified as a potential antitumor agent based on its high rate of bioactivation by human /"NQO1"/ and its selective cytotoxicity to cells containing elevated /"NQO1"/. RH1, a water-soluble analogue of MeDZQ synthesized in this work, was a better substrate for recombinant human /"NQO1"/ than the parent compound. RH1 was, correspondingly, more cytotoxic to human tumor cells expressing elevated /"NQO1"/ activity (H460 /"NSCLC"/ and HT29 human colon carcinoma), as measured by 3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium assay, than it was to cells deficient in /"NQO1"/ activity (H596 /"NSCLC"/ and BE human colon carcinoma). RH1 exhibited a greater selective toxicity (ratio of IC50s in H596:H460 and BE:HT29) to cells with elevated /"NQO1"/ activity relative to MeDZQ. Additionally, we report the establishment of a stable line of BE human colon carcinoma cells transfected with wild-type human /"NQO1"/ (BE-NQ7). BE cells are devoid of /"NQO1"/ activity due to a homozygous point mutation in the /"NQO1"/ gene. In comparison to the parental cell line, RH1, MeDZQ, and mitomycin C were significantly more cytotoxic to BE-NQ7 cells (17-, 7-, and 3-fold, respectively), confirming that the presence of /"NQO1"/ is sufficient to increase cytotoxicity of these antitumor quinones. These data suggest that RH1 may be an effective /"NQO1"/-directed antitumor agent for the therapy of tumors with elevated /"NQO1"/ activity, such as /"NSCLC"/. | [
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9865924 | A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent. | NAD(P)H:quinone oxidoreductase (NQO1; DT-diaphorase) is elevated in certain tumors, such as non-small cell lung cancer (NSCLC). Compounds such as mitomycin C and streptonigrin are efficiently bioactivated by NQO1 and have been used in an enzyme-directed approach to chemotherapy. Previously, 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone (MeDZQ) was identified as a potential antitumor agent based on its high rate of bioactivation by human NQO1 and its selective cytotoxicity to cells containing elevated NQO1. RH1, a water-soluble analogue of MeDZQ synthesized in this work, was a better substrate for recombinant human NQO1 than the parent compound. RH1 was, correspondingly, more cytotoxic to human tumor cells expressing elevated NQO1 activity (H460 NSCLC and HT29 human colon carcinoma), as measured by 3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium assay, than it was to cells deficient in NQO1 activity (H596 NSCLC and BE human colon carcinoma). RH1 exhibited a greater selective toxicity (ratio of IC50s in H596:H460 and BE:HT29) to cells with elevated NQO1 activity relative to MeDZQ. Additionally, we report the establishment of a stable line of BE human colon carcinoma cells transfected with wild-type human NQO1 (BE-NQ7). BE cells are devoid of NQO1 activity due to a homozygous point mutation in the NQO1 gene. In comparison to the parental cell line, RH1, MeDZQ, and mitomycin C were significantly more cytotoxic to BE-NQ7 cells (17-, 7-, and 3-fold, respectively), confirming that the presence of NQO1 is sufficient to increase cytotoxicity of these antitumor quinones. These data suggest that RH1 may be an effective NQO1-directed antitumor agent for the therapy of tumors with elevated NQO1 activity, such as NSCLC. | A new screening system for NAD(P)H:quinone oxidoreductase (/"NQO1"/)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a /"NQO1"/-directed antitumor agent. | NAD(P)H:quinone oxidoreductase (/"NQO1"/; /"DT-diaphorase"/) is elevated in certain tumors, such as non-small cell lung cancer (NSCLC). Compounds such as mitomycin C and streptonigrin are efficiently bioactivated by /"NQO1"/ and have been used in an enzyme-directed approach to chemotherapy. Previously, 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone (MeDZQ) was identified as a potential antitumor agent based on its high rate of bioactivation by human /"NQO1"/ and its selective /"cytotoxicity"/ to cells containing elevated /"NQO1"/. RH1, a water-soluble analogue of MeDZQ synthesized in this work, was a better substrate for recombinant human /"NQO1"/ than the parent compound. RH1 was, correspondingly, more cytotoxic to human tumor cells expressing elevated /"NQO1"/ activity (H460 NSCLC and HT29 human colon carcinoma), as measured by 3-(4,5-dimethylthiazol-2,5-diphenyl)tetrazolium assay, than it was to cells deficient in /"NQO1"/ activity (H596 NSCLC and BE human colon carcinoma). RH1 exhibited a greater selective /"toxicity"/ (ratio of IC50s in H596:H460 and BE:HT29) to cells with elevated /"NQO1"/ activity relative to MeDZQ. Additionally, we report the establishment of a stable line of BE human colon carcinoma cells transfected with wild-type human /"NQO1"/ (BE-NQ7). BE cells are devoid of /"NQO1"/ activity due to a homozygous point mutation in the /"NQO1"/ gene. In comparison to the parental cell line, RH1, MeDZQ, and mitomycin C were significantly more cytotoxic to BE-NQ7 cells (17-, 7-, and 3-fold, respectively), confirming that the presence of /"NQO1"/ is sufficient to increase /"cytotoxicity"/ of these antitumor quinones. These data suggest that RH1 may be an effective /"NQO1"/-directed antitumor agent for the therapy of tumors with elevated /"NQO1"/ activity, such as NSCLC. | [
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9886312 | A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV. | We describe a new variant of Bernard-Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIbalpha failed to support ristocetin-induced platelet agglutination and to bind two conformation-dependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIbalpha gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters. both with severe bleeding diathesis. were homozygous for the GPIX mutation: the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele. Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIbalpha, GPIX, GPIIb-IIIa and GMP-140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related. | A new variant of /"Bernard-Soulier syndrome"/ characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of /"GPIX"/ and GPV. | We describe a new variant of /"Bernard-Soulier syndrome"/ characterized by almost normal amounts of GPIb and severely reduced /"GPIX"/ and GPV. Despite surface expression, GPIbalpha failed to support ristocetin-induced platelet agglutination and to bind two conformation-dependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for /"GPIX"/ revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIbalpha gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters. both with severe bleeding diathesis. were homozygous for the /"GPIX"/ mutation: the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele. Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIbalpha, /"GPIX"/, GPIIb-IIIa and GMP-140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related. | [
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} | Yes |
9886312 | A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV. | We describe a new variant of Bernard-Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIbalpha failed to support ristocetin-induced platelet agglutination and to bind two conformation-dependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIbalpha gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters. both with severe bleeding diathesis. were homozygous for the GPIX mutation: the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele. Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIbalpha, GPIX, GPIIb-IIIa and GMP-140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related. | A new variant of Bernard-Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV. | We describe a new variant of Bernard-Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIbalpha failed to support ristocetin-induced platelet agglutination and to bind two conformation-dependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIbalpha gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters. both with severe /"bleeding"/ diathesis. were homozygous for the GPIX mutation: the members of the family with mild /"bleeding"/ diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele. Infusion of 1-desamino-8-D-arginine vasopressin normalized /"bleeding"/ time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIbalpha, GPIX, GPIIb-IIIa and /"GMP-140"/. Moreover, in one patient, normalization of /"bleeding"/ time and rise of von Willebrand factor plasma concentration did not seem to be directly related. | [
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