bluuebunny/crossref_metadata_2025 huggingface dataset:
Coding region intron/exon organization, alternative splicing, and X-chromosome inactivation of the KRAB/FPB-domain-containing human zinc finger gene ZNF41
Authors: Rosati M. , Franzé A. , Matarazzo M.R. , Grimaldi G.
Published: April 2003

ZNF41 belongs to a cluster of human zinc finger genes residing within a gene-rich region at Xp11.23. ZNF41 encodes a KRAB/FPB (Krüppel-associated/finger preceding box) domain, a potent transcription repression motif present in hundreds of vertebrate zinc finger protein genes, composed of two protein modules, A and B. Three introns, placed at identical positions in paralogous genes, interrupt four exons encoding the ZNF41 N-terminal amino acids, the KRAB/FPB-A and KRAB/FPB-B modules, and the remaining coding region adjoined to the C-terminal zinc finger domain. Since the KRAB/FPB-A and KRAB/FPB-B modules are encoded by dedicated exons in ZNF41 and paralogous genes, exon skipping may lead to differential usage of these modules in alternative gene products. RT-PCR analysis of ZNF41 mRNAs showed that, while skipping of the KRAB/FPB-A and/or KRAB/FPB-B exons was not detected, the use of alternative donor/acceptor sites upstream of the KRAB/FPB-A exon generates multiple ZNF41 transcripts potentially encoding polypeptides differing in the N-terminal region and expressed in different tissues. The expression pattern in cell hybrids containing either active or inactive X chromosomes indicates that ZNF41, which resides within a region of the X chromosome that includes genes that are both subject to and escape X-inactivation, is susceptible to X-chromosome inactivation.
Cloning of the murine Mist1 gene and assignment to mouse chromosome band 5G2–5G3
Authors: Pin C.L. , Lemercier C. , Konieczny S.F.
Published: April 2003

Mist1 is a basic helix-loop-helix (bHLH) transcription factor that is highly expressed in the adult pancreas. In this study, we isolated the mouse Mist1 gene and established its primary DNA sequence and complete genomic structure. Fluorescence in situ hybridization mapping located the Mist1 gene to the telomere of mouse chromosome 5 at position 5G2–5G3, an area which is syntenic to human chromosome 13q and which contains several additional pancreatic regulatory genes including IPF1 and CDX2.
Colon polyps: a damaged developmental system and a precursor to cancer
Authors: White R.L.
Published: April 2003

The observation that the attenuated form of adenomatous polyposis coli (AAPC) has a different mutational spectrum in both the adenomatous polyp and the carcinoma than the classical form of APC has led to the hypothesis that AAPC alleles retain some residual APC activity associated with a greatly reduced number of polyps. It is suggested that further progression to carcinoma may be dependent upon either loss of the AAPC allele (loss of heterozygosity), followed by an APC mutation in the wild-type allele, or the occurrence of APC mutations within both the AAPC and wild-type alleles.
Population genomics in Sardinia: a novel approach to hunt for genomic combinations underlying complex traits and diseases
Authors: Siniscalco, M. , Robledo, R. , Bender, P.K. , Carcassi, C. , Contu, L. , Beck J.C.
Published: April 2003

The availability of highly polymorphic markers permits testing whether complex traits and diseases result from genomic interactions between nonallelic normal variants at separate loci. Such variants may be identified by deviations from the expected distributions of alleles at a high number of polymorphic loci, when individuals with the phenotype of interest are compared to normal controls of the same breeding unit, provided that both groups share the same remote ancestry and had no ancestors in common for the last three to four generations. The circumstances needed for such studies are ideally met on the island of Sardinia. The recurrent finding of the same type of association in separate breeding units between the phenotype of interest and a given genotype should allow a distinction between true genetic identity by descent and randomly occurring identities, as these will be obviously different in separate breeding units. The availability of several breeding units located in sharply different ecological environments will permit assessment of the role of nature/nurture factors in the degree of manifestation of each newly discovered genotype/phenotype association. A pilot study to evaluate the proposed strategy has been carried out in the Sardinian village of Carloforte, a community of about 8,000 individuals who have remained genetically homogeneous. Fifty-five control samples have been genotyped with six tetranucleotide microsatellites and with a subset of the 400 markers contained in the ABI PRISM linkage mapping panel, version 2. The allele frequencies for these microsatellite markers have been determined for these 55 individuals and compared to those from a random sampling of subsets of these 55 persons. For the six tetranucleotide microsatellites, a subset of as few as 20 people displayed the same allele frequency distributions as observed with the original 55 unrelated individuals. In conclusion, when samples are chosen from the same breeding unit, the number of individuals sufficient to draw the genomic profile of an isolated population can be relatively small. Likewise, the number of probands with the phenotype of interest can be even smaller when they are ascertained with the same genealogical criteria as the normal controls. By comparing the genomic profile of the probands to a fraction of the control samples within each of several separate breeding units of common remote ancestry, the search for genotype/phenotype association for mono- and multifactorial traits and diseases should be simplified and yield unequivocal results.
The human gene for the poly(A)-specific ribonuclease (PARN) maps to 16p13 and has a truncated copy in the Prader-Willi/Angelman syndrome region on 15q11→q13
Authors: Buiting K. , Körner C. , Ulrich B. , Wahle E. , Horsthemke B.
Published: April 2003

The deadenylation nuclease or poly(A)-specific ribonuclease (PARN) is a 3′ exonuclease, which degrades the poly(A)-tail of eukaryotic mRNA molecules. By DNA sequence analysis of cDNA and genomic clones, fluorescence in situ hybridization, and reverse transcriptase-PCR, we have determined that the active human PARN gene is located in 16p13 and that a truncated copy lacking the 5′ end is located in 15q11. The truncated gene maps close to a copy of the D15F37 gene family at the proximal Prader-Willi/Angelman (PWS/AS) deletion breakpoint region. Other copies of the F37 gene family are located at the distal PWS/AS deletion breakpoint region and on 16p11.2. Although PARN and F37 gene sequences are present on 15q and 16p, our data suggest that the synteny of these loci is the result of independent genetic events.
Comparative FISH mapping on Z chromosomes of chicken and Japanese quail
Authors: Suzuki T. , Kansaku N. , Kurosaki T. , Shimada K. , Zadworny D. , Koide M. , Mano T. , Namikawa T. , Matsuda Y.
Published: April 2003

Using direct R-banding fluorescence in situ hybridization, we assigned five functional genes—growth hormone receptor (GHR), prolactin receptor (PRLR), spleen tyrosine kinase (SYK), aldolase B (ALDOB), and muscle skeletal receptor tyrosine kinase (MUSK)—to the chicken Z chromosome. SYK and MUSK were newly localized to the chicken Z chromosome in this study. GHR and PRLR were situated close to each other on the short arm of the chicken Z chromosome, as are their counterparts on human chromosome 5. SYK, MUSK, and ALDOB, which have been mapped to human chromosome 9, were localized to the long arm of the chicken Z chromosome. Thus, the present results indicate the presence of conserved synteny between the chicken Z chromosome and human chromosomes 5 and 9. Using the same method, four of the genes (GHR, PRLR, ALDOB, and MUSK) were assigned to the Japanese quail Z chromosome. The locations of these four Z-linked genes were conserved between chicken and Japanese quail. The results support the notion that the avian Z chromosome and the mammalian X chromosome did not evolve from a common ancestral linkage group.
Cloning, expression, and mapping of PDCD9, the human homolog of Gallus gallus pro-apoptotic protein p52
Authors: Carim L. , Sumoy L. , Nadal M. , Estivill X. , Escarceller M.
Published: April 2003

We report the sequence, tissue distribution, and chromosome location of a novel gene, PDCD9 (programmed cell death 9). PDCD9 is the mammalian counterpart of the Gallus gallus pro-apoptotic protein p52. The human cDNA has an open reading frame of 1,314 nucleotides and was predicted to encode a protein of 438 amino acids with a calculated mass of 50 kDa. The protein sequences of chicken, mouse, and human PDCD9 are remarkably conserved. PDCD9 mRNA is expressed ubiquitously in adult tissues, displaying a stronger signal in heart, skeletal muscle, kidney, and liver. PDCD9 was mapped to chromosome 5q11.
M31, a murine homolog of Drosophila HP1, is concentrated in the XY body during spermatogenesis
Authors: Motzkus D. , Singh P.B. , Hoyer-Fender S.
Published: April 2003

The formation of the sex vesicle, or XY body, during male meiosis and pairing of the sex chromosomes are thought to be essential for successful spermatogenesis. Despite its cytological discovery a century ago, the mechanism of XY body formation, particularly heterochromatinization of the sex chromosomes, has remained unclear. The HP1 class of chromobox genes are thought to encode proteins involved in the packaging of chromosomal DNA into repressive heterochromatin domains, as seen, for example, in position-effect variegation. Study of the distribution of a murine HP1-like chromodomain protein, M31, during spermatogenesis revealed spreading from the tip of the XY body in mid-stage pachytene spermatocytes to include the whole of the XY body in late-pachytene spermatocytes. We also demonstrate that the formation of the XY body during spermatogenic progression in neonatal mice coincides with the expression of a novel nuclear isoform of M31, M31p21. These results support the view that a common mechanistic basis exists for heterochromatin-induced repression, homeotic gene silencing, and sex-chromosome inactivation during mammalian spermatogenesis.
Genomic cloning and chromosomal localization of the mouse Mab21l2 locus
Authors: Wong R.L.Y. , Wong H.T. , Chow K.L.
Published: April 2003

A second mouse gene related to the nematode mab-21 gene has been isolated. This gene, Mab21l2, encodes a transcript with an open reading frame discretely organized in a single exon. It shares 93.3% and 55.5% amino acid identity with the human and worm mab-21 respectively. FISH analysis determined that this gene is on chromosome 3 at a position between bands 3E3 and 3F1. This newly identified mouse gene will be useful in future examination of mab-21 gene function in vertebrate models.
Preferential S-phase pairing of the imprinted region on distal mouse chromosome 7
Authors: Riesselmann L. , Haaf T.
Published: April 2003

Fluorescence in situ hybridization (FISH) has been used to visualize the spatial orientation of homologous chromosome regions in interphase nuclei of exponentially growing mouse fibroblasts. Simultaneous labeling of replicating DNA with the halogenated base analog 5-bromodeoxyuridine (BrdU) shows preferential somatic pairing of the imprinted region on distal mouse chromosome 7 during the S phase of the cell cycle. Trans-interactions between oppositely imprinted chromosome regions may be important for the maintenance of imprinting.
Nondisjunction in human sperm: comparison of frequencies in acrocentric chromosomes
Authors: Martin R.H. , Rademaker A.W.
Published: April 2003

Acrocentric chromosomes may be particularly predisposed to nondisjunction because of the frequency of trisomy for these chromosomes in human spontaneous abortions and liveborns. Studies of aneuploidy in human sperm have provided data on only a few acrocentric chromosomes, with evidence that chromosome 21 has a significantly increased frequency of disomy. To determine whether other acrocentric chromosomes have a higher frequency of nondisjunction or if chromosome 21 is anomalous, disomy frequencies for chromosomes 13 and 22 were studied by fluorescence in situ hybridization (FISH) analysis of 51,043 sperm nuclei from five normal men for whom the frequency of disomy for chromosomes 15 and 21 was known. The mean frequency of disomy for chromosome 13 (0.19%) did not differ significantly from that for other autosomes; however, the frequency of disomy 22 (1.21%) was significantly elevated (P < 0.001, Mantel-Haenszel χ2 test). The G-group chromosomes (Nos. 21 and 22) also showed a significantly increased frequency of disomy (0.75%) compared to acrocentric D-group chromosomes (viz., chromosomes 13 and 15; 0.15%) (P < 0.001, Mantel-Haenszel χ2 test) and other autosomes (chromosomes 1, 2, 4, 9, 12, 13, 15, 16, 18, and 20; 0.13%) studied in the same men (P < 0.001, Mantel-Haenszel χ2 test).
Mapping of the CCXCR1, CX3CR1, CCBP2 and CCR9 genes to the CCR cluster within the 3p21.3 region of the human genome
Authors: Maho A. , Bensimon A. , Vassart G. , Parmentier M.
Published: April 2003

Human CC-chemokine receptor genes are known to be clustered. The detailed structure of this cluster was established by radiation hybrid mapping, and organization of BAC contigs by fluorescence hybridization on combed genomic DNA. A main cluster of six genes (CCR1, CCR3, CCRL2, CCR5, CCR2 and CCXCR1), covered by four BACs, was mapped to the 3p21.3 region of the human genome. Five other genes (CCR9, CCBP2, CX3CR1, CCR8 and CCR4) were found to be spread over a relatively large region between this main cluster and the 3p telomere.
Evolutionary disruptions of human syntenic groups 3, 12, 14, and 15 in Ateles paniscus chamek (Platyrrhini, Primates)
Authors: Canavez F.C. , Moreira M.A.M. , Bonvicino C.R. , Parham P. , Seuánez H.N.
Published: April 2003

Comparative gene assignments of 18 markers, based on analyses of somatic cell hybrids and previous data in the literature, indicated that human (HSA) syntenic groups 3, 12, 14, and 15 are dissociated in the spider monkey species Ateles paniscus chamek (APC). Markers present in HSA 3p were allocated to APC 3 and APC 9. The HSA 12 cluster was split into two syntenic groups, one mainly including HSA 12p markers in APC 16 and the other, including HSA 12q markers, in APC 2p. The HSA 14q cluster split into three syntenic groups, corresponding to APC 2q, APC 6, and APC 12. Finally, the HSA 15 cluster split into two syntenic groups, APC 2q and APC 3. Comparisons with previous gene assignments and human SROs led to the tentative postulation of rearrangements having occurred during the evolutionary divergence of man and A. paniscus chamek. Chromosome painting data in the congeneric species A. geoffroyi, other New World and Old World primates, and several representative non-primate animals were compared in an attempt to delineate the ancestral and derived conditions underlying the evolutionary rearrangement of syntenic groups in mammals.
Identification of the mouse β`-COP golgi component as a spermatocyte autoantigen in scleroderma and mapping of its gene Copb2 to mouse Chromosome 9
Authors: Tarsounas M. , Heng H.H.Q. , Ye C.J. , Pearlman R.E. , Moens P.B.
Published: April 2003

In an immunological screening of a mouse testicular cDNA library with a human CREST serum we isolated five overlapping cDNA clones encoding the mouse homolog of a Golgi coatomer complex protein (accession number AF043120), designated β′-COP in bovine and p102 in humans. We generated antibodies against this protein which specifically recognize the Golgi apparatus of mouse spermatocytes. FISH analyses assigned the β′-COP gene Copb2 to mouse Chromosome 9, region E3–F1. Our results demonstrate that CREST sera can contain antibody components against Golgi proteins as well as against nuclear proteins.
Karyotype and chromosome location of characteristic tandem repeats in the pufferfish Tetraodon nigroviridis
Authors: Fischer C. , Ozouf-Costaz C. , Roest Crollius H. , Dasilva C. , Jaillon O. , Bouneau L. , Bonillo C. , Weissenbach J. , Bernot A.
Published: April 2003

Karyotype analysis of Tetraodon nigroviridis, a pufferfish of the family Tetraodontidae with a small compact genome (385 Mb) which is currently being investigated in our laboratory, indicates that this species has 2n = 42 chromosomes. The small chromosome size (the largest pair measuring less than 3 μm) has complicated accurate chromosome pairing based on morphology alone. DAPI staining, however, provides a banding-like pattern. Because of quantitative variations of some heterochromatin classes, the chromosome formula can not be established precisely, but is estimated to include approximately 20 meta- or submetacentric chromosomes and 22 subtelocentric chromosomes. A centromeric satellite, telomeric repeats, and the major and minor rRNA clusters have been localized unequivocally by FISH. As a result, the 28S and 5S rDNA sequences can be used as chromosome-specific probes.
Chromosome localization and characterization of the mouse and human zinc finger protein 265 gene
Authors: Adams D.J. , van der Weyden L. , Kovacic A. , Lovicu F.J. , Copeland N.G. , Gilbert D.J. , Jenkins N.A. , Ioannou P.A. , Morris B.J.
Published: April 2003

The chromosome location and pattern of expression of the gene encoding the zinc finger protein 265 (alias “Zis”) in human (ZNF265) and mouse (Zfp265) was determined. By interspecific backcross analysis, we mapped Zfp265 to mouse chromosome 3q. ZNF265 was localized to human chromosome 1p31 by fluorescence in situ hybridization. Since discovery of Zfp265 (in rat) came from studies of changes in renin expression in kidney cell lines, we examined the cell specificity of expression in kidney and also determined hybridization of cDNA with RNA in other tissues. We found that expression was not confined to renin mRNA-containing cells but was ubiquitous. Moreover, the fact that highly conserved homologs of ZNF265p exist in lower organisms (e.g., C4SR in Xenopus), suggests that this protein may have a generalized role in posttranscriptional mechanisms in various cell types and species.
X;Y translocation revealed by chromosome microdissection and FISH in fertile XY females in the Brazilian rodent Akodon montensis
Authors: Fagundes V. , Christoff A.U. , Scalzi-Martin J. , Hozier J. , Moreira-Filho C.A. , Yonenaga-Yassuda Y.
Published: April 2003

In a Brazilian population of the neotropical rodent Akodon montensis we found five sex-reversed XY females. These animals were cytogenetically analyzed by chromosome painting using species-specific DNA probes from the Y chromosome, generated by chromosomal microdissection and subsequent use of the degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR). The results showed a chromosome complement with an apparently normal Y chromosome and an X chromosome carrying a translocation that encompasses a large portion of the Y chromosome (seemingly the entire Y). Ovarian histology suggested that these females are fertile. Amplification of the SRY HMG box sequence by PCR shows that at least one copy of the Sry gene is present in the A. montensis XY females. Based on our findings, we suggest that the breakpoint of the X;Y translocation probably altered an X-linked sex-determining locus (or loci), blocking testicular organogenesis in the XY females. Further studies are necessary to determine the precise location and role of this putative sex-determining chromosomal region. Genetic mechanisms of XY sex reversal in A. montensis populations are discussed.
Cloning, characterization, and physical mapping of the canine Prop-1 gene (PROP1): exclusion as a candidate for combined pituitary hormone deficiency in German shepherd dogs
Authors: Lantinga-van Leeuwen I.S. , Kooistra H.S. , Mol J.A. , Renier C. , Breen M. , van Oost B.A.
Published: April 2003

Abnormalities in the genes encoding Pit-1 and Prop-1 have been reported to cause combined pituitary hormone deficiency (CPHD) in mice and humans. In dogs, a similar phenotype has been described in the German shepherd breed. We have previously reported that the Pit-1 gene (POU1F1) is not mutated in affected German shepherd dogs. In this study, we report the isolation and mapping of the canine Prop-1 gene (PROP1), and we assessed the involvement of PROP1 in German shepherd dog dwarfism. The canine PROP1 gene was found to contain three exons, encoding a 226 amino acid protein. The deduced amino acid sequence was 79% and 84% homologous with the mouse and human Prop-1 protein, respectively. Using fluorescence in situ hybridization, PROP1 was mapped to canine chromosome 11. Further mapping with a canine radiation hybrid panel showed co-localization with the polymorphic DNA marker AHT137. Sequence analysis of genomic DNA from dwarf German shepherd dogs revealed no alterations in the PROP1 gene. Moreover, linkage analysis of AHT137 revealed no co-segregation between the PROP1 locus and the CPHD phenotype, excluding this gene as candidate for canine CPHD and providing a new spontaneous model of hypopituitarism.
Murine chromosome 16 telomeric region, homologous with human chromosome 21q22, contains the osmoregulatory Na+/myo-inositol cotransporter (SLC5A3) gene
Authors: McVeigh K.E. , Mallee J.J. , Lucente A. , Barnoski B.L. , Wu S. , Berry G.T.
Published: April 2003

The murine Na+/myo-inositol cotransporter (SLC5A3) gene (Slc5a3) was cloned, the restriction sites mapped, and the coding region sequenced. Similar to other mammalian counterparts, including human, the gene has a single coding exon, with an open reading frame of 2.2 kb. The predicted protein of 718 amino acids is also highly conserved, compared to other mammalian homologs. Using fluorescence in situ hybridization, Slc5a3 was localized to the telomeric region of mouse chromosome 16, which is syntenic to human chromosome 21q22. An increased Slc5a3 copy number may explain the increased levels of myo-inositol in the brains of trisomy 16 mice and the increased rate of transport of myo-inositol into cultured neurons derived from trisomy 16 mice.
Mouse linkage cytogenetics (L-C) probes
Authors: Liechty M.C. , Clase A.C. , Puschus K.L. , Aytay S. , Carpio C.M. , Hall B.K. , Hozier J.C.
Published: April 2003

We have identified 149 hybridization probes at 10-cM intervals in the mouse and have confirmed their order and linkage by fluorescence in situ hybridization. These probes represent a new resource for mapping in the mouse and can be used to correlate linkage and cytogenetic maps, to map novel sequences to within a few centimorgans, to relate cytogenetic abnormalities to the genetic map, and to make cross-species comparisons.
Delineation and physical separation of novel translocation breakpoints on chromosome 1p in two genetically closely associated childhood tumors
Authors: Steenman M.J.C. , Zijlstra N. , Kruitbosch D.L. , Wiesmeijer C. , Larizza L. , Voûte P.A. , Westerveld A. , Mannens M.M.A.M.
Published: April 2003

Sporadic childhood tumors associated with Beckwith-Wiedemann syndrome (BWS) all show abnormalities of the same region on chromosome 11. In addition to chromosome 11, other chromosome regions are affected in some of these tumor types. In this study we analyzed the region on chromosome 1p involved in the etiology of BWS-associated tumors, Wilms tumor, rhabdomyosarcoma, and hepatoblastoma. For this purpose we determined the location of two novel translocation breakpoints in this chromosome region in cells from a Wilms tumor and cells from a rhabdomyosarcoma. We constructed a map of the region and found that both breakpoints are separated by at least 875 kb. We identified a PAC clone which crosses the rhabdomyosarcoma breakpoint and found several exons within this clone. We established that this breakpoint is located proximal to the PAX7 gene and, therefore, identified a new region involved in the etiology of rhabdomyosarcomas.
Fine mapping of the human preprocortistatin gene (CORT) to neuroblastoma consensus deletion region 1p36.3→p36.2, but absence of mutations in primary tumors
Authors: Ejeskär K. , Abel F. , Sjöberg R.-M. , Bäckström J. , Kogner P. , Martinsson T.
Published: April 2003

The processed product of the human gene preprocortistatin, the peptide cortistatin-17 (hCST-17), bears a strong structural resemblance to the peptide somatostatin (SST), which has an identical receptor binding domain. CST has affinity to all known SST receptor (SSTR) subtypes. Expression of both SST and its receptors has been shown in previous studies to have biological and clinical significance in neuroblastomas, with a putative role in tumor differentiation and apoptosis in vivo. In this work we have employed radiation hybrid mapping and BAC physical mapping to map the human preprocortistatin gene (CORT) to chromosome region 1p36.3→p36.2, close to the genetic marker D1S244. D1S244 defines the centromeric border of the smallest region of overlap of deletion in our primary neuroblastoma material. We have also defined the genomic sequence of the gene by BAC sequencing and found that preprocortistatin consists of two exons divided by a 1-kb intron. Two polymorphic sites, neither of which causes amino acid exchange, have been detected in the coding region of the gene. Expression studies showed that preprocortistatin is expressed in neuroblastomas of all different stages, as well as in ganglioneuromas. Through genomic sequencing we made mutation analyses of exonic sequences in 49 primary neuroblastomas of all different stages, but no mutations could be detected.
Chromosomal localization1 of GPR48, a novel glycoprotein hormone receptor like GPCR, in human and mouse with radiation hybrid and interspecific backcross mapping
Authors: Loh E.D. , Broussard S.R. , Liu Q. , Copeland N.G. , Gilbert D.J. , Jenkins N.A. , Kolakowski Jr. L.F.
Published: April 2003

We report the chromosomal localization in both mouse and human of a novel G-protein-coupled receptor, GPR48, which resembles glycoprotein hormone receptors, that may be implicated in Wilms tumor deletion syndromes such as WAGR. This receptor forms a novel sub-family of glycoprotein hormone-like GPCRs. We have mapped this receptor to human chromosome 11p14→p13 by several approaches, including radiation hybrid and interspecific backcross mapping, and show that GPR48 is close to BDNF. This data differs from the recently published mapping of LGR4 (5q34→q35.1) (Hsu et al., 1998). Additionally, we show that Gpr48 and Bdnf are tightly linked on mouse chromosome 2, in a region with conserved synteny to human 11p14→p13.
The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours
Authors: Morris C.M. , Haataja L. , McDonald M. , Gough S. , Markie D. , Groffen J. , Heisterkamp N.
Published: April 2003

The closely related small GTP-binding proteins Rac1, Rac2, and Rac3 are part of a larger Rho subfamily of Ras proteins. Because disruption of Ras signaling pathways is relevant to the pathogenesis of a wide variety of cancers, it is important to clearly define the structural and functional characteristics of the participating proteins and their encoding genes. Rho subfamily members are involved in a range of signal transduction pathways relevant to cell growth, differentiation, motility, and stress, and Rac proteins are now recognised as a necessary component of Ras-mediated cellular transformation. We previously mapped RAC3 to chromosome band 17q23→ q25, a region that contains a number of candidate tumour suppressor genes. Because of its oncogenic potential, we have now further refined the location of this gene. Here we confirm that RAC3 maps to chromosome band 17q25.3 and further show that it maps some distance telomeric of a well-characterised minimal breast and ovarian candidate tumour suppressor gene region, BROV. The genomic structure of RAC3, including exon and intron boundaries, is also presented.
Detection of chromosomal imbalances in leiomyosarcoma by comparative genomic hybridization and interphase cytogenetics
Authors: Otaño-Joos M. , Mechtersheimer G. , Ohl S. , Wilgenbus K.K. , Scheurlen W. , Lehnert T. , Willeke F. , Otto H.F. , Lichter P. , Joos S.
Published: April 2003

Leiomyosarcomas comprise a group of malignant soft-tissue tumors with smooth-muscle differentiation. In this study, 14 cases of leiomyosarcoma were screened for changes in relative chromosome copy number by comparative genomic hybridization. A high number of imbalances (mean, 16.3; range, 6–26) was detected, with chromosomal gains occurring about twice as much as losses. The most frequent gains were found in 5p15, 8q24, 15q25→q26, 17p, and Xp (43% to 50%), whereas the most frequent losses were found in 10q and 13q (50% and 78%, respectively). Twenty high-level amplifications affecting 15 different chromosomal subregions were detected in nine different tumors. In three leiomyosarcomas, sequences on chromosome arm 17p were found to be highly amplified, with a minimal overlapping region on subbands 17p12→p11. We further discovered that the Smith-Magenis syndrome critical region on 17p11.2 is included in the 17p amplicons of two leiomyosarcoma cases. Using probes flanking this genetically unstable region, a mean of 14 and 22 signals per nucleus, respectively, was detected in both leiomyosarcomas by fluorescence in situ hybridization. In conclusion, this analysis identifies a number of characteristic chromosomal imbalances in leiomyosarcomas and provides evidence for the localization of potential oncogenes and tumor suppressor genes active in leiomyosarcoma genomes.
DNA methylation and chromosome instability in lymphoblastoid cell lines
Authors: Vilain A. , Bernardino J. , Gerbault-Seureau M. , Vogt N. , Niveleau A. , Lefrançois D. , Malfoy B. , Dutrillaux B.
Published: April 2003

In order to gain more insight into the relationships between DNA methylation and genome stability, chromosomal and molecular evolutions of four Epstein-Barr virus–transformed human lymphoblastoid cell lines were followed in culture for more than 2 yr. The four cell lines underwent early, strong overall demethylation of the genome. The classical satellite-rich, heterochromatic ,juxtacentromeric regions of chromosomes 1, 9, and 16 and the distal part of the long arm of the Y chromosome displayed specific behavior with time in culture. In two cell lines, they underwent a strong demethylation, involving successively chromosomes Y, 9, 16, and 1, whereas in the two other cell lines, they remained heavily methylated. For classical satellite 2–rich heterochromatic regions of chromosomes 1 and 16, a direct relationship could be established between their demethylation, their undercondensation at metaphase, and their involvement in non-clonal rearrangements. Unstable sites distributed along the whole chromosomes were found only when the heterochromatic regions of chromosomes 1 and 16 were unstable. The classical satellite 3–rich heterochromatic region of chromosomes 9 and Y, despite their strong demethylation, remained condensed and stable. Genome demethylation and chromosome instability could not be related to variations in mRNA amounts of the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B and DNA demethylase. These data suggest that the influence of DNA demethylation on chromosome stability is modulated by a sequence-specific chromatin structure.
No deleterious mutations in the FOXJ1 (alias HFH-4) gene in patients with Primary Ciliary Dyskinesia (PCD)
Authors: Maiti A.K. , Bartoloni L. , Mitchison H.M. , Meeks M. , Chung E. , Spiden S. , Gehrig C. , Rossier C. , DeLozier-Blanchet C.D. , Blouin J.-L. , Gardiner R.M. , Antonarakis S.E.
Published: April 2003

The transcription factor FOXJ1 (alias HFH-4 or FKHL13) of the winged-helix/forkhead family is expressed in cells with cilia or flagella, and seems to be involved in the regulation of axonemal structural proteins. The knockout mouse Foxj1–/– shows abnormalities of organ situs, consistent with random determination of left-right asymmetry, and a complete absence of cilia. The human FOXJ1 gene which maps to chromosome 17q, is thus an excellent candidate gene for Kartagener Syndrome (KS), a subphenotype of Primary Ciliary Dyskinesia (PCD), characterized by bronchiectasis, chronic sinusitis and situs inversus. We have collected samples from 61 PCD fami- lies, in 31 of which there are at least two affected individuals. Two families with complete aciliogenesis, and six families, in which the affected members have microsatellite alleles concordant for a locus on distal chromosome 17q, were screened for mutations in the two exons and intron-exon junctions of the FOXJ1 gene. No sequence abnormalities were observed in the DNAs of the affected individuals of the selected families. These results demonstrate that the FOXJ1 gene is not responsible for the PCD/KS phenotype in the families examined.
Mini review: Form and function in the human interphase chromosome
Authors: Chevret E. , Volpi E.V. , Sheer D.
Published: April 2003

A key feature of interphase chromosomes is their compaction into discrete “territories” in the nucleus. In this review, we focus on the compartmentalization of the genome conferred by this organization and evaluate our current understanding of the role of large-scale chromatin folding in the regulation of gene expression. We examine evidence for the hypothesis that transcription occurs at the external surfaces of chromosomes and follow its evolution to include transcription at the surfaces of chromatin-rich domains within chromosomes. We also present prevailing views regarding the details of large-scale chromatin folding and the functional relationship between chromatin and the enigmatic nuclear matrix.
Characterization of three hairy cell leukemia- derived cell lines (ESKOL, JOK-1, and Hair-M) by multiplex-FISH, comparative genomic hybridization, FISH, PRINS, and dideoxyPRINS
Authors: Lindbjerg Andersen C. , Østergaard M. , Nielsen B. , Pedersen B. , Koch J.
Published: April 2003

Hairy cell leukemia (HCL) is a chronic B-lymphocyte leukemia. Due to the proliferative inertia of the malignant cells, HCL-derived cell lines are an important tool for studies on this disease. We have elaborated the karyotypes of three HCL-derived cell lines, ESKOL, JOK-1, and Hair-M, by combining a range of molecular cytogenetic techniques, including multiplex (multicolor) fluorescence in situ hybridization (M-FISH), comparative genomic hybridization (CGH), conventional FISH, primed in situ labeling (PRINS), and dideoxyPRINS. We found ESKOL to be monoclonal with a single chromosome aberration, der(7)t(3;7)(q26.3;q31). JOK-1 also ap- peared to be monoclonal, having the karyotype 48,XY,der(4) t(1;4)(1pter→p32::4qter→pter), der(6)(6qter→p22::q12→ qter),+der(7)t(7;11)(7pter→q21::11p15→pter),der(8)t(5;8;12) (5pter→p14::12p11.2→p12::8q12→q21::8?cen→→24.?2), der(14)t(8;14)(8qter→q24.?2::14q32.3→pter),+20. These karyotypes differ from the original descriptions of ESKOL and JOK-1. The Hair-M cells analyzed by us were found to be peritetraploid with numerous chromosomal rearrangements. The cell line was also found to be multiclonal. On this basis, we do not regard the Hair-M cell line to be suitable for HCL studies.
Molecular cloning, expression and chromosome location of the human pelota gene PELO
Authors: Shamsadin R. , Adham I.M. , von Beust G. , Engel W.
Published: April 2003

The pelota gene of Drosophila melanogaster encodes a protein that was found to be included in cell cycle regulation. Mutations were found to result in spermatogenic arrest, female sterility and disturbances in the patterning of the eye. Here we describe the cloning of the human pelota cDNA (PELO) that encodes a 385-amino-acid protein. Southern blot and fluorescence in situ hybridization analyses revealed that PELO is present as a single copy gene in the human genome and is localized on chromosome 5q11.2. Northern blot analysis revealed the presence of a 1.6-kb transcript in all tissues studied and an additional 2.0-kb transcript in testis.
Clinical and Ultrasonic Long-Term Results of Percutaneous Transluminal Carotid Angioplasty
Authors: Schoser Benedikt G.H. , Becker Veit U. , Eckert Bernd , Zeumer Hermann , Thie Andreas
Published: April 2003

Experience of the long-term outcome of patients treated with carotid balloon angioplasty is limited. Therefore, we prospectively analyzed the ultrasonic and clinical features of 29 patients with complete follow-up data beyond 24 months, evaluated from 1989 through 1996 from our carotid angioplasty cohort of 106 patients. Mean follow-up time was 33 months. For up to 78 months postangioplasty, 23 patients with 24 angioplasties (77%) had no further neurological sequelae. Single ipsilateral amaurosis fugax or TIA events occurred in 3 patients. Recurrent ipsilateral amaurosis fugax or TIA events were noted twice in 2 patients. No patient suffered an ipsilateral stroke. Fifteen angioplasties (50%) remained with normal ultrasound (stenosis <50%), mild restenosis (50–70%) occurred in 12 angioplasties (40%), and severe restenosis (>70%) in 3 angioplasties (10%). Only in 2 of 15 patients clinical complications were related to the occurrence of ipsilateral restenosis above 50%. Until now, rigorous and careful evaluation of patients and clinical and ultrasonic follow-up have been essential for the estimation of the long-term efficacy of carotid angioplasty. It should be noted that carotid angioplasty is a new technique in evolution, with a high potential improving the technical results.
Can a Clinical Classification of Stroke Predict Complications and Treatments during Hospitalization?
Authors: Pinto Amélia N. , Melo Teresa P. , Lourenço Maria Eduarda , Leandro Maria José , Brázio Ana , Carvalho Leonor , Soares Franco António , Ferro José M.
Published: April 2003

The predictive value of the Oxfordshire Community Stroke Project ischemic stroke classification for acute stroke complications, therapeutic interventions and disability at discharge was investigated in 297 consecutive first-ever acute stroke patients. More than one medical complication (odds ratio, OR = 2.2), fever (OR = 2.5) and dependency (Rankin grade >2) at discharge (OR = 2.3) were more frequent in intracerebral hemorrhage patients. Fever and urinary tract infections were the most common complications among ischemic stroke patients. Both were more frequent in total anterior circulation infarct (TACI) patients (OR = 11.5 and OR = 3.7). Neurological deterioration was observed in about 10% of TACI and posterior circulation infarct (POCI) patients. Dependency at discharge was more frequent in TACI patients (OR = 10.3). Logistic regression analysis identified ischemic stroke subgroups (OR = 8.4) and medical complications (OR = 3.8) as predictors of poor outcome (Rankin score ≥4). A clinical classification is useful to predict possible medical and neurological complications in the acute phase, death and dependency at discharge.
Painful Oculomotor Nerve Palsy – A Presenting Sign of Internal Carotid Artery Stenosis
Authors: Höllinger Peter , Sturzenegger Matthias
Published: April 2003

We report a 72-year-old patient presenting acute painful partial left IIIrd nerve palsy with pupillary involvement. Due to the patient’s age and mild hyperlipidemia a microangiopathic ischemic origin was assumed after a compressive or inflammatory cause had been excluded by magnetic resonance imaging, blood and cerebrospinal fluid analyses. Carotid ultrasound examination disclosed a high-grade stenosis of the ipsilateral internal carotid artery (ICA). In the absence of diabetes mellitus, other significant vascular risk factors and leukoencephalopathy indicative of advanced arteriosclerotic disease, we suggest a pathogenetic role of the ICA stenosis in ischemic IIIrd nerve palsy. The frequency of a IIIrd nerve palsy as the presenting symptom in patients with ICA stenosis as well as the frequency of an ICA stenosis being the cause in patients with isolated IIIrd nerve palsy is not well documented in the literature. Both seem to be rare but may be underestimated. We advocate cervicocerebral ultrasound examination in patients presenting IIIrd nerve palsy with no obvious or a presumed ischemic cause.
Cerebral Vein Thrombosis in a Case with Thromboangiitis obliterans
Authors: Bischof Felix , Kuntz Reinhard , Melms Arthur , Fetter Michael
Published: April 2003

Thromboangiitis obliterans is a chronic inflammatory vessel disease that involves predominantly the small and medium-sized arteries and veins of the distal extremities. Appearance and cessation of symptoms are closely related to patterns of tobacco consumption. That cerebral arteries can also be involved is shown by reports of rare cases in which cerebral artery occlusion led to infarction. We report on a 28-year-old man with thromboangiitis obliterans who developed extensive cerebral vein thrombosis after a single episode of cigarette smoking following several years of nonsmoking. Despite extensive evaluation, no other known cause or predisposition of cerebral vein thrombosis could be found. This case suggests that cerebral veins can be involved in thromboangiitis obliterans and patients with thromboangiitis obliterans might be at risk for cerebral vein thrombosis.
Carotid Artery Stenting in Patients at Surgical High Risk: Clinical and Ultrasound Findings
Authors: Griewing B. , Brassel F. , von Smekal U. , Al Ahmar M.T. , Kessler Ch.
Published: April 2003

Angioplasty and stenting (A/S) provide an alternative for patients with simultaneous severe cardiac and cerebrovascular disease, or with medical illnesses which carry a high perioperative risk. We conducted A/S in 20 high-risk patients (15 males, 5 females, mean age = 64.5 years, range = 49–83 years) with symptomatic (n = 16) and asymptomatic (n = 4) high-grade stenosis (>70%, NASCET criterion) of the internal carotid artery. Patients had neurological examinations before, during and after the procedure. Color-coded duplex sonography was performed before and 24 h and every 3 months after the procedure; the 3-month examination also included cerebral angiography. The mean degree of stenosis was reduced from 85.75 ± 7.47 to 8.0 ± 22.09% in angiography. In an 18-month follow-up with color-coded duplex sonography the effects of the A/S could be visualized effectively: 2 with local, transient vasospasms, 1 with asymptomatic occlusion, 2 carotid arteries with remaining stenosis of 50% and 2 with minimal hyperplasia within the stent. In conclusion, in patients with a high perioperative risk, A/S is a therapeutic alternative to surgery.
A Comparison of Cerebral Hemodynamic Parameters between Transient Monocular Blindness Patients, Transient Ischemic Attack Patients and Control Subjects
Authors: Rutgers D.R. , Donders R.C.J.M. , Vriens E.M. , Kappelle L.J. , van der Grond J.
Published: April 2003

Purpose: To assess whether patients with transient monocular blindness (TMB) and patients with hemispheric transient ischemic attacks (hTIA) differ from each other with respect to cerebral hemodynamic parameters. Methods: Seventeen TMB patients and 23 hTIA patients with a moderate to severe stenosis or an occlusion of the internal carotid artery (ICA) underwent magnetic resonance (MR) angiography, 1H MR spectroscopy and transcranial Doppler sonography. Thirty-one control subjects were investigated to obtain reference values for the MR investigations. Quantitative flow was measured in the ICAs, the basilar artery and the middle cerebral arteries (MCA). Metabolic changes in the MCA territory were studied by assessing N-acetyl-aspartate (NAA)/choline ratios and prevalences of lactate. The prevalence of collateral flow was assessed in the circle of Willis and the ophthalmic arteries. The vasomotor reactivity was studied by measuring the CO2 reactivity of the MCA territories. Results: Quantitative flow in the cerebropetal arteries and the MCAs did not differ between TMB patients and hTIA patients. Also patterns of collateral flow, prevalence of lactate and CO2 reactivity were similar. The mean ipsilateral NAA/choline ratio was lower in hTIA patients compared with TMB patients (p < 0.01), and was predominantly correlated with symptomatology (p < 0.01), i.e. whether patients had TMB or hTIA, and not with ipsilateral MCA flow (p = 0.2) or ipsilateral CO2 reactivity (p = 0.7). Conclusion: The results of this study indicate that there are no cerebral hemodynamic differences between TMB patients and hTIA patients. It is therefore unlikely that hemodynamic factors account for differences in clinical characteristics between the two patient groups.
Delayed Intrahemispheric Remote Hypometabolism
Authors: Iglesias S. , Marchal G. , Viader F. , Baron J.-C.
Published: April 2003

Although ‘intrahemispheric diaschisis’ (i.e. a hypometabolism affecting the cerebral hemisphere ipsilateral to but remote from the infarct) may classically exacerbate acute-stage neurological deficit and influence early recovery, it has been studied only rarely. Out of a series of 30 patients with first-ever middle cerebral artery (MCA) territory stroke, we analyzed the data from 19 survivors investigated by 15O positron emission tomography (PET) both in the acute (within 5–18 h of clinical onset) and subacute (approximately 3 weeks later) stage, and for whom chronic-stage CT coregistered with PET was available to assess infarct topography and size. Orgogozo’s MCA scale was used to assess neurological deficits at the time of, and recovery between, the PET studies. Oxygen consumption was obtained for both PET sessions for the whole ipsilateral hemisphere (excluding ventricles and infarct), as well as for the thalamus and the occipital and mesial-prefrontal cortex (i.e. potentially deafferented tissue outside the MCA territory). In all regions except the occipital cortex, the oxygen consumption significantly decreased between the first and the second session, without significant correlation with the concomitant changes in MCA scores. However, acute-stage mesial-prefrontal metabolism was significantly correlated with neurological recovery. Also, both the hemisphere and the mesial-prefrontal metabolism at the second session were significantly correlated with both infarct size and concomitant MCA scores, but the latter relationship became insignificant when infarct size was taken into account. This study reveals no evidence of acute intrahemispheric diaschisis after MCA territory stroke in man. However, it documents for the first time a phenomenon of delayed intrahemispheric remote hypometabolism developing while the patients clinically recover. Because the degree of this secondary phenomenon is a function of infarct size, a mechanism of degeneration of the damaged neuron terminals is likely. Finally, contrary to other reports, neurological recovery was not a function of thalamic hypometabolism, but appeared to be influenced by acute-stage mesial-frontal metabolism, perhaps because this region is part of a network that has an important compensatory role in motor recovery.
Advances in Genetics: Issues for US Racial and Ethnic Minorities: An Asian American and Pacific Islander Perspective
Authors: Lin-Fu JaneS.
Published: April 2003

In 1998, racial and ethnic minorities reached 27.5% of the United States (US) population, but remain severely underrepresented in the genetics community. Among minorities, Asian Americans and Pacific Islanders, almost two thirds of whom are foreign-born, have been the fastest growing but least understood population. This paper describes the recent dramatic growth of US minorities, and challenges the genetics community to become sensitive to issues that concern minority communities and to assure equity in all facets of genetics, including public policies, basic research, clinical studies, service programs, professional training, public education, epidemiological surveys, and debate over ethical, legal and psychosocial issues.