bluuebunny/crossref_metadata_2025 huggingface dataset:
Asthma and atopy – a total genome scan for susceptibility genes
Authors: Haagerup A. , Bjerke T. , Schiøtz P. O. , Binderup H. G. , Dahl R. , Kruse T. A.
Published: March 2003

Background:  Allergic asthma is an increasingly common disease of complex inheritance. Several studies have suggested candidate regions, but genetic heterogeneity, ethnic differences and varying study designs may in part explain the lack of identified and confirmed susceptibility genes. Investigation of different populations will further clarify the topic. We therefore evaluated allergic asthma and increased total and specific IgE in 39, 45 and 57 sib‐pairs from 100 Danish allergy families.

Methods:  Affected sib‐pairs meeting a narrow phenotype definition were selected for the three phenotypes atopy, allergic asthma and increased total IgE. We performed a total genome scan using 446 microsatellite markers and obtained nonparametric linkage results from the MAPMAKER/SIBS computer program.

Results:  Our study revealed four candidate regions (MLS > 2) on chromosome 1p36, 3q21–q22, 5q31 and 6p24–p22, and 15 candidate regions (1 < MLS < 2) that may contain susceptibility genes for asthma and atopy. We did not find linkage to the candidate genes TNF‐β, FcER1β and Il4R‐α, except for weak support for linkage of the asthma phenotype to TNF‐β (MLS = 1.18).

Conclusions:  We found evidence for two new asthma and atopy loci, 1p36 and 3q21–q22, and supported linkage in the Danish population to seven previously reported candidate regions.
Rapid release of Ole e 1 from Olive pollen using different solvents
Authors: Carnés J. , Fernández‐Caldas E. , Boluda L. , Casanovas M. , Sastre J. , Bernal M. Lluch , Blanca M.
Published: March 2003

Background:  Solubility is an important characteristic of allergenic molecules. The aim of this study was to investigate the solubility of Ole e 1, a major allergen of Olea europaea, using different solvents.

Material and methods:  Olea europaea pollen was placed in a glass column and extracted using three different solvents: deionized water, phosphate buffer 0.01 M (PBS) and normal saline (NaCl 0.9%). Several fractions were collected after extraction with each solvent and pooled based on individual protein content. Each fraction corresponded to a different elution profile, as determined by linear regression analysis. After 130 min of extraction, the pollen that remained in the column was further extracted overnight. A control olive pollen extract was also prepared with each solvent. The antigenic and allergenic profiles of all the eluted and pooled fractions were analysed by SDS‐PAGE and inmmunoblots. Protein and Ole e 1 content and the amount of protein needed to produce 50% inhibition were also calculated. Ten patients were skin prick tested with the fractions obtained with deionized water.

Results:  Four elution profiles were obtained using deionized water as the extracting solution and three with the two other solvents. The three solvents produced different kinetics of allergen release. Ole e 1 was rapidly released when water was used, obtaining a total of 256 µg of Ole e 1/ml after only 7 min of extraction (fraction EC1). Using PBS, or NaCl 0.9%, the release of Ole e 1 started after 4 and 9 min of extraction, respectively. The highest amount ofOle e 1 was eluted after 44 and 26 min, with a total concentration of 162 and 203 µg of Ole e 1/ml, respectively. The presence of Ole e 1 in each phase was verified by SDS‐PAGE and immunoblot analyses.

Conclusions:  The extracting solution seems to determine the antigenic profile of olive pollen extracts. Ole e 1 is rapidly released from the pollen grain after extraction in deionized water. The solubility seems to be affected by the use of other solvents. These techniques could be used to manipulate the Ole e 1 content in O. europaea extracts.
The importance of maximal airway response to methacholine in the prediction of wheezing development in patients with cough‐variant asthma
Authors: Koh Y. Y. , Park Y. , Kim C. K.
Published: March 2003

Background: A significant proportion of patients diagnosed with cough‐variant asthma eventually manifest classic asthma signs, such as wheezing and dyspnea. The aim of this study was to investigate whether the degree of airway hypersensitivity and/or the level of maximal airway response can predict the development of wheezing in subjects with cough‐variant asthma.

Methods: At study initiation, a high‐dose methacholine inhalation test was performed to measure provocative concentration causing a 20% fall (PC20) in forced expiratory volume in 1 s (FEV1) and maximal airway response. Each person was evaluated regularly every 3 months for 4 years and also on the occasion of wheezing being perceived for the first time.

Results: Of the 48 patients available in the follow‐up period, 21 (Group 1) developed clinical wheezing, while 27 (Group 2) did not. There was no significant difference in PC20 levels between the two groups. The level of maximal airway response, however, was significantly higher in Group 1 than in Group 2. The score test for trend revealed a significant association between the future development of wheezing and the level of maximal airway response (P = 0.007), but not the level of methacholine PC20 (P = 0.423).

Conclusions: The level of maximal airway response, rather than the degree of airway hypersensitivity, may be an important risk factor for the future development of classic asthma in patients with cough‐variant asthma.
Allergologic exploration of germins and germin‐like proteins, a new class of plant allergens
Authors: Jensen‐Jarolim E. , Schmid B. , Bernier F. , Berna A. , Kinaciyan T. , Focke M. , Ebner C. , Scheiner O. , Boltz‐Nitulescu G.
Published: March 2003

Background:  Germins and the related germin‐like proteins (GLPs) are glycoproteins expressed in many plants in response to biotic and abiotic stress. To test the potential impact of germins and GLPs, recombinant germin from Triticum aestivum (tGermin) and GLPs from Arabidopsis thaliana (tGLP), both produced in transformed tobacco plants, were used.

Methods:  Sera from 82 patients with type I allergy to birch, grass or mugwort pollen and/or wheat were tested in immunoblot for IgE binding to tGermin and tGLP, and the IgE reactivity after chemical and enzymatic deglycosylation was analysed. The biological activity of tGermin and tGLP was determined in a histamine release assay and in skin prick testing (SPT).

Results:  In an immunoblotting assay, 24 out of 82 tested sera (29.26%) from allergic patients showed IgE‐binding to tGermin, and 18 of these sera (21.95%) displayed also IgE‐binding to tGLP. The deglycosylation experiments indicated that glycan moieties contribute significantly to the IgE‐binding of tGermin and tGLP. Both tGermins and tGLP induced specifically histamine release in an invitro assay as well as in SPT.

Conclusion:  Our in vitro and in vivo findings demonstrate that germin and GLPs are capable to bind IgE most likely via carbohydrate determinants, and represent allergenic molecules.
Urinary metabolites of histamine and leukotrienes before and after placebo‐controlled challenge with ASA and food additives in chronic urticaria patients
Authors: Di Lorenzo G. , Pacor M. L. , Vignola A. M. , Profita M. , Esposito‐Pellitteri M. , Biasi D. , Corrocher R. , Caruso C.
Published: March 2003

Background: The recovery of mediator metabolites from urine has the potential to provide a rapid, safe, and easily available index of release of mediators. We aimed to determine urinary metabolites of both histamine and leukotrienes (LTs) in patients affected by chronic urticaria (CU).

Methods: Twenty patients with CU were studied. They were selected on the basis of double‐blind placebo‐controlled challenge (DBPC) with acetyl salicylic acid (ASA) and food additives. Ten patients (group B) were negative to both challenges. Ten patients (group C) presented urticaria and/or the appearance of angioedema during or 24 h after challenge, with reactions to ASA (five patients) or food additives (five patients). We recruited 15 healthy volunteers as controls (group A). During a second challenge, groups B and C were challenged double‐blind with a single dose of ASA, or a specific food additive, or placebo. The healthy group was challenged only with a placebo (talc capsule). Patients in groups B and C were challenged twice: with placebo (as groups B1 and C1) and with ASA (groups B2 and C2) or food additives (C2). Four samples of urine were collected; one during the night before the specific or sham challenge (baseline), and three at 2, 6 and 24 h after the challenge. Urinary methylhistamine (N‐MH) and LTE4 were analyzed and normalized for urinary creatinine.

Results: For urinary N‐MH at baseline, there was a significant difference only between group A and groups B1, B2, C1 and C2 (A vs. B1, P < 0.0001; A vs. B2, P < 0.0001; A vs. C1, P < 0.0001; A vs. C2, P < 0.0001). We detected a significant variation in urinary methylhistamine excretion only in group C2 after 2 h, 6 h and 24 h (P < 0.0001). However, no variations were observed in N‐MH excretion rate in the other groups (A, B1, C1) after challenge with placebo, and in B2 after challenge with ASA 20 mg. For urinary LTE4 at baseline no differences were found between the mean values for the different groups. After specific challenge, only C2 patients showed significantly increased excretion rates of urinary LTE4 compared with the other groups challenged with placebo (A, B1, C1), or ASA (B2) (P < 0.0001). No significant correlation was seen between urinary LTE4 and methylhistamine excretion rate in any patients.

Conclusion:  Our results show that urinary excretion of N‐MH and LTE4 is different for CU patients without ASA or food hypersensitivity, compared to those with CU with ASA or food additive hypersensitivity after specific challenge.
ERASM, a pharmacoepidemiologic survey on management of intermittent allergic rhinitis in every day general medical practice in France
Authors: Demoly P. , Allaert F.‐A. , Lecasble M. ,   PRAGMA
Published: March 2003

Background: The actual management of intermittent allergic rhinitis is still little known about, despite the disease being very prevalent. We used a cross‐sectional survey to address this issue in everyday general medical practice in France.

Methods: A total of 1321 general practitioners enrolled 3026 patients consulting for a spring exacerbation of allergic rhinitis. Both doctors and patients filled out a specific questionnaire on allergic rhinitis.

Results: These patients consulted their doctor two‐and‐a‐half weeks, on average, after the onset of their symptoms. They were bothered for an average of six days per week (5.9 ± 1.7 days) and for two months per year (8.7 ± 7.7 weeks) by symptoms which largely exceed the ENT (ear, nose and throat) field, with ocular symptoms (51.7%), pharyngeal irritation (39.0%), cough (30.8%), or respiratory discomfort (17.9%). Of these patients 79.2% had some impairment of their professional life and 91.8% of their daily life. Fifty percent of patients knew to what allergens they were allergic; only 11.1% had additional laboratory tests and 10.3% had subsequent specialist consultation (for most this was with an allergologist). Prescribed drugs were oral antihistamines (92.4%) and nasal glucocorticosteroids (45.2%). Prescriptions were written for a duration of six weeks on average. Seventy‐nine percent of patients considered that the information they had received was adequate and easy to understand, but 58.2% of patients would have liked more advice. Furthermore, only 54.7% followed their doctor's prescription scrupulously, and 44% used frequent self‐medication.

Conclusions: Intermittent allergic rhinitis is a real health problem because of its increasing prevalence, the induction of impaired quality of life and loss of performance, especially at work. General practitioners play a major role in this disorder; they make the diagnosis, start the treatment, give the relevant information, and monitor most of the patients.
HLA‐DR‐dependent increased mannan‐induced lymphoproliferative response in atopic eczema dermatitis syndrome
Authors: Savolainen J. , Kosonen J. , Kortekangas‐Savolainen O. , Yssel H. , Bousquet J.
Published: March 2003

Background: In yeast‐sensitive atopic eczema dermatitis syndrome (AEDS), yeast mannan induces highly elevated specific IgE levels and lymphoproliferative responses. In healthy individuals the involvement of both human leukocyte antigen (HLA)‐dependent T‐cell activation and non‐HLA‐dependent activation, e.g. by crosslinking of the cell surface mannose receptors, has been suggested. In the present study the HLA dependence and the role of crosslinking in the lymphoproliferative response to mannan in AEDS has been analyzed.

Methods: Twenty patients with AEDS and 12 controls with no history of allergic diseases were included in the study. Mannan from Candida albicans was prepared according to the Cetavlon method. Following isolation using Ficoll‐Hypaque, peripheral blood mononuclear cells (PBMC) were incubated with the mannan preparation in the absence and presence of different concentrations of neutralizing anti‐HLA antibodies and α‐methylmannoside for 6 days and proliferative responses were measured by 3H‐thymidine incorporation and scintilloradiography.

Results: In AEDS patients with elevated mannan‐specific serum IgE, the C. albicans mannan induced lymphoproliferation. Mannan‐induced lymphoproliferative responses could be inhibited, dose‐dependently, by neutralizing anti‐HLA‐DR, but not anti‐HLA‐DQ antibodies in AEDS patients and healthy controls. The addition of α‐methylmannoside, that blocks binding to mannose receptors, inhibited lymphoproliferative responses in a dose‐dependent way by 50% only in healthy controls, but not in AEDS patients. Levels of inhibition of the proliferation by α‐methylmannoside correlated inversely with the yeast‐ and mannan‐specific IgE levels.

Conclusions: These results show that in healthy subjects yeast mannan activates lymphocytes both in an HLA‐DR‐dependent manner and as a result of direct crosslinking of the cell surface. However, in AEDS the elevated lymphoproliferative response is HLA‐DR‐dependent, although only a slight proportion of this response results from direct crosslinking.
IgE‐binding and cross‐reactivity of a new 41 kDa allergen of codfish
Authors: Das Dores S. , Chopin C. , Romano A. , Galland‐Irmouli A.‐V. , Quaratino D. , Pascual C. , Fleurence J. , Guéant J.‐L.
Published: March 2003

Background:  A 41‐kDa IgE‐reactive protein (p41) was purified from raw cod extract. This protein is homologous to an aldehyde phosphate dehydrogenase (APDH). The present study aims to evaluate the IgE‐binding and the cross‐reactivity of this protein in 13 patients allergic to codfish.

Methods:  IgE binding of sera from 13 patients allergic to codfish was tested by Sepharose RIA and by Western blot.

Results:  Among the 13 patients, only 4 had specific IgE to APDH detected by APDH‐Sepharose RIA. The two patients who had the highest level of specific IgE to human APDH also had a class 5–6 CAP‐RAST IgE level to codfish, but two other patients with a class 5 had a negative APDH‐Sepharose IgE‐RIA. Relative content of APDH was higher in extracts of commercial nonfrozen fish, compared to pre rigor mortis, post rigor mortis and frozen commercial codfish. A high homology of codfish APDH was found with the corresponding human enzyme. A significant inhibition of APDH‐Sepharose by human and, to a lesser extent, by rabbit APDH was observed. Western blot of APDH codfish extract showed two bands at 41 and 36 kDa, respectively.

Conclusions:  We have characterized a new allergen from codfish, which had a high level of homology in different species. The p41 relative content of extracts from nonfrozen codfish was higher than in the other samples assessed.
t(1;18)(q32.1;q22.1) associated with genitourinary malformations
Authors: Frizell Edward R , Sutphen Rebecca , Jr Frank B Diamond , Sherwood Margaret , Overhauser Joan
Published: March 2003

We report a male infant who has impaired penile development, hypospadias, and mild developmental delay with a 46,XY,t(1;18)(q32.1; q22.1) karyotype. Fluorescent in situ hybridization (FISH) was performed to more precisely map the translocation breakpoint. The translocation breakpoint maps to a region that has been implicated in genitourinary malformations in the 18q‐ syndrome. This case report suggests that a gene involved in genitourinary development maps at or near the chromosome 18 translocation breakpoint.
Confirmation of linkage in X‐linked infantile spasms (West syndrome) and refinement of the disease locus to Xp21.3‐Xp22.1
Authors: Bruyere Helene , Lewis ME Suzanne , Wood Stephen , MacLeod Patrick J , Langlois Sylvie
Published: March 2003

The syndrome of infantile spasms, hypsarrhythmia, and mental retardation (West syndrome) is a classical form of epilepsy, occurring in early infancy, which is etiologically heterogeneous. In rare families, West syndrome is an X‐linked recessive condition, mapped to Xp11.4‐Xpter (MIM 308350). We have identified a multi‐generation family from Western Canada with this rare syndrome of infantile spasms, seen exclusively in male offspring from asymptomatic mothers, thereby confirming segregation as an X‐linked recessive trait. Using highly polymorphic microsatellite CA‐repeat probes evenly distributed over the entire X chromosome, linkage to markers DXS7110, DXS989, DXS1202, and DXS7106 was confirmed, with a maximum LOD score of 3.97 at a Θ of 0.0. The identification of key recombinants refined the disease‐containing interval between markers DXS1226 and the adrenal hypoplasia locus (AHC). This now maps the X‐linked infantile spasms gene locus to chromosome Xp21.3‐Xp22.1 and refines the interval containing the candidate gene to 7.0 cM. Furthermore, this interval overlaps several loci previously linked with either syndromic or non‐syndromic X‐linked mental retardation (XLMR), including one recognized locus implicated in neuroaxonal processing (radixin, RDXP2). Collectively, these studies lend strong support for the presence of one or more genes intrinsic to brain development and function, occurring within the critical interval defined between Xp21.3‐Xp22.1.
Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history
Authors: Tonin Patricia N , Mes‐Masson Anne‐Marie , Narod Steven A , Ghadirian Parviz , Provencher Diane
Published: March 2003

The breast cancer susceptibility genes, BRCA1 and BRCA2, differ in their contribution to ovarian cancer. Recently, founder mutations in each of these genes were identified in Canadian breast cancer and breast–ovarian cancer families of French ancestry. We have examined the prevalence of the founder mutations in a series of 113 French Canadian women with ovarian cancer unselected for family history. Germline mutations were found in eight of 99 invasive carcinomas and in none of the 14 tumors of borderline malignancy. Five cases carried the BRCA1 C4446T mutation and two cases carried the BRCA2 8765delAG mutation which are the most common mutations that have been described in French Canadian breast cancer and breast–ovarian cancer families. All of these cases reported a family history of at least one first‐degree relative with breast cancer, diagnosed below age 60 years, or with ovarian cancer. The identification of founder BRCA1 and BRCA2 mutations in ovarian cancer cases unselected for family history can facilitate carrier detection when the expected yield of a comprehensive screen may be low.
Dysmorphic phenotype and neurological impairment in 22 retinoblastoma patients with constitutional cytogenetic 13q deletion
Authors: Baud Olivier , Cormier‐Daire Valérie , Lyonnet Stanislas , Desjardins Laurence , Turleau Catherine , Doz François
Published: March 2003

We describe the facial dysmorphic phenotype and the neurological development of a series of 22 retinoblastoma patients sharing a cytogenetically detectable 13q deletion in a retrospective and longitudinal study. In most of the cases, high‐resolution banding analysis, morphological analysis, and assessment for neurodevelopmental outcome, as well for organ malformations, were performed.

Chromosomal rearrangement involving the RB1 gene included 20 13q interstitial deletions (including 16 de novo deletions) and two de novo translocations. The most prominent dysmorphic abnormalities were anteverted ear lobes (90%), a high and broad forehead (85%), and a prominent philtrum (65%). This phenotype was associated with severe mental retardation and/or motor impairment at age 2 years in 69% of patients and correlated with the size and the location of the 13q deletion. The survival rate of our series (91%) was not different from that usually seen in retinoblastoma patients.
Germline mosaicism in X‐linked myotubular myopathy
Authors: Häne Bernhard G , Curtis Rogers R , Schwartz Charles E
Published: March 2003

X‐linked myotubular myopathy (XLMTM; OMIM310400) is a congenital muscle disorder characterized by severe hypotonia and respiratory insufficiency. The disorder was mapped to Xq28 by linkage studies and the MTM1 gene was isolated by positional cloning. The gene product is a 603 amino acid protein named myotubularin. A small domain in its sequence shows high homology to a consensus active site of tyrosine phosphatases, a diverse class of proteins involved in signal transduction, control of cell growth, and differentiation. In this report, two brothers affected with XLMTM are shown to have a point mutation (G1187A) in exon 11 of the MTM1 gene. Surprisingly, their mother does not have this mutation in her lymphocytes. Therefore, she likely has a germline mosaicism. As this is the third report of germline mosaicism in XLMTM, the finding has important implications for genetic counseling.
Aicardi–Goutières syndrome: monogenic recessive disease, genetically heterogeneous disease, or multifactorial disease?
Authors: Fauré Sabine , Bordelais Isabelle , Marquette Catherine , Rittey Chris , Campos‐Castello Jaime , Goutières Françoise , Ponsot Gérard , Weissenbach Jean , Lebon Pierre
Published: March 2003

Aicardi–Goutières syndrome (AGS) is a severe progressive familial encephalopathy, which is usually diagnosed shortly after birth. Using the principle of homozygosity mapping, genome‐wide screening of five consanguineous families was performed to search for a homozygous region shared by all affected individuals. A total of 364 markers with an average spacing of 9.9 cM were genotyped, but no homozygous region common to all affected individuals could be found. Regions of homozygosity in affected sibs could only be identified within each family individually. This may reflect genetic heterogeneity, possibly related to clinical heterogeneity, since several syndromes are clinically difficult to distinguish from AGS. Involvement of a small number of genes and/or of an external factor, such as infection, may also explain the absence of a homozygous region common to all affected individuals.
Fetal anticonvulsant syndrome and mutation in the maternal MTHFR gene
Authors: Dean John Cs , Moore Susan J , Osborne Aileen , Howe Jonathan , Turnpenny Peter D
Published: March 2003

Around 6% of infants born to mothers taking anticonvulsants have malformations, including neural tube defects, and a further proportion show developmental delay in later childhood. Three commonly used anticonvulsants, carbamazepine, phenytoin and sodium valproate, interfere with folic acid metabolism. We investigated the common 677 C>T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in samples from 57 patients and their parents and 152 controls to determine its contribution to the risk of fetal anticonvulsant syndrome. The 677 C>T mutation frequency was significantly higher in the mothers than in the controls, but there was no significant difference in 677 C>T frequency in the patients or in the fathers. Genotype frequencies in the mothers were significantly different from controls, there being an excess of 677 C>T homozygotes. Amongst the patients, there was an apparent excess of heterozygotes (not statistically significant), and the fathers were not significantly different from controls. Mutation in the MTHFR gene in a mother taking sodium valproate, phenytoin or carbamazepine during pregnancy is associated with fetal anticonvulsant syndrome in her offspring. The skewed distribution of genotypes in the affected children probably reflects the association of fetal anticonvulsant syndrome with the maternal genotype.
Genetic and segregation analysis of congenital cataract in the Indian population
Authors: Vanita Jai Rup , Singh Daljit , Singh
Published: March 2003

Congenital cataract is a major cause of blindness in children, and there is wide variation in the few reports available on the frequencies of its different inheritance patterns. Two hundred and fifty‐two families with congenital cataract belonging to 13 different states of India, were clinically and genetically investigated to study their inheritance and segregation patterns. Twenty‐one percent of the cases were autosomal recessive, 15% autosomal dominant, 63% were simplex cases, and in the remaining cases the inheritance pattern was not clear. A high incidence of consanguinity (50.9%) was observed in autosomal recessive cases. Out of 340 affected individuals, 222 (65.3%) were males and 118 (34.7%) were females. Segregation analysis showed good agreement in autosomal dominant and recessive families and the data are indicative of the prevalence rate for different inheritance patterns of congenital cataract within the Indian population.
Impact of age and body size on inter‐individual variation in measures of lipid metabolism: influence of gender and apolipoprotein E genotype
Authors: Lussier‐Cacan S , Bolduc A , Xhignesse M , Niyonsenga T , Connelly PW , Sing CF
Published: March 2003

This study was undertaken in 1695 adult subjects (870 women and 825 men) in order to further document the complexity of the influence of the apolipoprotein (apo) E genotypes on the mean levels and intragenotypic variability of seven measures of lipid metabolism. In addition, the statistical relationships between variability in these traits and variation in age, body mass index (BMI) and waist‐to‐hip ratio (WHR) were assessed. The contribution of variation in age and body size to inter‐individual variation was found to be dependent on context, defined by gender and apo E genotype. Our findings are consistent with the reality that it is neither genes nor environments, but their interactions that are responsible for the variation in risk of cardiovascular disease.
Down syndrome: genetic recombination and the origin of the extra chromosome 21
Authors: Hassold Terry , Sherman Stephanie
Published: March 2003

Despite the clinical importance of trisomy 21, we have been ignorant of the causes of meiotic nondisjunction of chromosome 21. Recently, however, genetic mapping studies of trisomy 21 families have led to the identification of the first molecular correlate of human nondisjunction; i.e. altered levels and positioning of meiotic recombinational events. Specifically, increases in 0 exchange events or in distal‐only or pericentromeric exchanges are significantly increased in trisomy 21‐generating meioses. These observations have led to the idea that chromosome 21 nondisjunction requires ‘two hits’: first, the establishment in prophase I of a ‘vulnerable’ bivalent and second, abnormal processing of the bivalent at metaphase I or II.
A rapid fluorescent multiplexed‐PCR analysis (FMPA) for founder mutations in the BRCA1 and BRCA2 genes
Authors: Kuperstein Graciela , Foulkes William D , Ghadirian Parviz , Hakimi Jalil , Narod Steven A
Published: March 2003

Mutations of the BRCA1 and BRCA2 genes account for approximately 80% of hereditary breast/ovarian cancer families, but the size of these two genes makes mutation analysis time‐consuming and technically challenging. In some populations such as the Ashkenazi Jewish and the French‐Canadian, a small number of recurrent founder mutations account for the majority of mutations in cancer families. We have therefore developed two rapid genetic screening tests, which allow us to detect three frequent frameshift mutations in the Ashkenazi Jewish population and five frameshift mutations in the French‐Canadian population. These fluorescent non‐radioactive methods permit the simultaneous detection of multiple mutations by generating multiplexed PCR‐amplified gene fragments, and by discriminating these on the basis of their size in a denaturing polyacrylamide gel. Using these methods, we were able to correctly identify all mutants in a blinded analysis of 276 DNA samples, including 30 derived from paraffin‐embedded tumor samples and 10 from buccal‐cell brushes, with no false positive or false negative results.  These techniques designed for the direct detection of recurrent mutations in the BRCA1 and BRCA2 genes, have the advantages of being efficient, sensitive, cost‐effective, and are applicable to large scale screening for epidemiologic studies.
Trends in the frequencies of consanguineous marriages in the Israeli Arab community
Authors: Jaber Lutfi , Halpern Gabrielle J , Shohat Tamy
Published: March 2003

To assess the trends in the frequency of consanguineous marriages in the Israeli Arab population in the last 40 years, we conducted a two‐part study. For the first part, we re‐analyzed data from a nationwide study carried out in 1992, and for the second part, we undertook a new survey in 1998 in four locations: Taibe, Tira, Kalansuwa and Kafr Bara. Data regarding the frequency of consanguineous marriage in these four locations for the years 1961–1985 was extracted from the original survey, and for the years 1986–1998, from new questionnaires.  The frequency of consanguineous marriage was highest in the period 1961–1965 (50.6%), but by the period 1981–1985 it had decreased to 40.6%. Over the whole time span of the 1992 study, a significant decrease was observed between the periods 1961–1975 and 1976–1985 (p<0.0001).  In the four‐location study, there was a significant decrease in the frequency of consanguineous marriage from 52.9% in the period 1961–1970 to 32.8% in the period 1991–1998 (p=0.0006). We conclude that the custom of consanguineous marriage in the studied population is still extremely high, and preventive measures should be taken to decrease its frequency and associated complications.
No evidence of uniparental disomy 2, 6, 14, 16, 20, and 22 as a major cause of intrauterine growth retardation
Authors: Kotzot D , Lurie IW , Méhes K , Werder E , Schinzel A
Published: March 2003

Intrauterine growth retardation (IUGR) is defined as length and/or weight below the 10th percentile. Etiology and, consequently, long‐term outcome are extremely heterogeneous with chromosomal abnormalities found in up to 7%. Recently, uniparental disomy (UPD), i.e. the inheritance of both homologues of one pair of chromosomes from only one parent, was found in an increasing number of children with IUGR. Particularly, UPD of chromosome 7 was found in up to 10% of patients with IUGR and/or a phenotype of primordial growth retardation or Silver‐Russell syndrome (SRS), but also UPD of chromosomes 2, 6, 14, 16, 20, and 22 was reported in single cases with IUGR. To evaluate impact and relevance of UPD in children with IUGR we investigated 23 sporadic cases with IUGR subsequently diagnosed as primordial growth retardation (n=13) or SRS (n=10) by molecular methods for UPD of chromosomes 2, 6, 14, 16, 20, and 22. No instance of UPD was found. Inheritance of all chromosomes investigated was biparental in all cases. Therefore, we conclude that UPD of these chromosomes is not a major cause of IUGR.
Familial t(6;21)(p21.1;p13) translocation associated with male‐only sterility
Authors: Paoloni‐Giacobino A , Kern1 I , Rumpler Y , Djlelati R , Morris MA , Dahoun SP
Published: March 2003

A 38‐year‐old male with primary infertility was referred for cytogenetic investigation. Karyotype analysis revealed a 46,XY,t(6;21)(p21.1;p13) translocation. The Ag‐nucleolar organizer regions (NORs) banding technique demonstrated that the 21p NORs were retained in the derivative and actively transcribed. Family studies showed that three brothers, two sisters and their mother carried the t(6;21). All carrier males suffered from primary infertility with severe oligoasthenoteratospermia or azoospermia, whereas at least two of the three carrier women were fertile. The region of the translocation breakpoint was narrowed down cytogenetically and by fluorescence in situ hybridisation as 21p13 and 6p21.1. Southern blot analysis showed that the gene ZNF165, which maps to this region and which is specifically expressed in the testis, was not disrupted by the translocation. However, studies performed on testicular biopsy showed spermatocyte meiosis anomalies. We discuss the possible mechanisms by which the translocation might affect meiosis in spermatogenesis and lead to infertility.
Kyphomelic dysplasia: a rare form of semilethal skeletal dysplasia
Authors: Prasad C , Cramer BC , Pushpanathan C , Crowley MC , Ives EJ
Published: March 2003

Kyphomelic dysplasia is a rare form of generalized skeletal dysplasia with about 15 cases described so far in the literature. We present the clinical, radiological, and pathological findings of an antenatally detected female fetus affected with this disorder. The differential diagnoses of prenatal and perinatal semilethal skeletal dysplasias and salient features of documented cases of kyphomelic dysplasia are presented.
The molecular basis of cystic fibrosis in South Africa
Authors: Goldman A , Labrum R , Claustres M , Desgeorges M , Guittard C , Wallace A , Ramsay M
Published: March 2003

The spectrum of CFTR mutations in three South African populations is presented. To date, a total of 192 white patients (384 chromosomes) with confirmed CF have been tested. ΔF508 accounts for 76% of the CF chromosomes in this group, with 3272−26A→G, 394delTT and G542X occurring at the following frequencies: 4, 3.6 and 1.3%, respectively. A further 11 mutations account for 6% of CF chromosomes. A total of 91% of the CF‐causing mutations can now be detected in the South African white population. Haplotype analysis suggests a founder effect in South Africans of European origin for the two common CFTR mutations, 3272−26A→G and 394delTT.  The diagnosis of CF has been confirmed in 14 coloured and 12 black CF patients. In the coloured population, both the ΔF508 and 3120+1G→A mutations occur at appreciable frequencies of 43 and 29%, respectively. In the black population, the most common CF‐causing mutation, the 3120+1G→A mutation, occurs at an estimated frequency of 46%. Four other mutations have been detected, resulting in the identification of a total of 62.5% of mutations in this population.
Shakespeare as a geneticist1
Authors: Berg Jm
Published: March 2003

There are frequent allusions in Shakespeare's plays to physical and mental characteristics and qualities of individuals that often reflect genetic and related insights, ideas and implications with a bearing on the determination of these phenotypes. Quotations from the plays with comments are presented here to indicate varied perceptions in these regards that Shakespeare brilliantly conveyed some 400 years ago through many of his ‘dramatis personae’.
Identification of the Arg1086His mutation in the alpha subunit of the voltage‐dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia
Authors: Stewart Sl , Hogan K , Rosenberg H , Fletcher Je
Published: March 2003

Individuals from a large North American population were screened for the presence of the mutation in the α1 subunit of the voltage‐dependent calcium channel (CACNA1S) that has recently been associated with malignant hyperthermia (MH). This Arg1086His mutation was screened for in 154 MH normal (MHN) individuals and 112 MH susceptible (MHS) individuals, who were diagnosed by the North American protocol of the in vitro contracture test. PCR and restriction enzyme analysis was used to test for the mutation. The Arg1086His mutation in the CACNA1S was not found in any of the MHN individuals. In contrast, two related individuals (grandfather and grandson, father and son of the MH proband) among the MHS group exhibited this mutation. However, a third MHS individual in the same family (granddaughter, cousin of the grandson) did not exhibit this mutation. These results indicate that this mutation may be associated with MH in this family. Genetic alterations in the CACNA1S associated with MH are present in approximately 1% of this North American MHS population.
Fibrillin‐1 (FBN1) gene frameshift mutations in Marfan patients: genotype–phenotype correlation
Authors: Pepe G , Giusti B , Evangelisti L , Porciani MC , Brunelli T , Giurlani L , Attanasio M , Fattori R , Bagni C , Comeglio P , Abbate R , Gensini GF
Published: March 2003

Marfan syndrome (MFS) is a multisystemic disease associated with mutations in the fibrillin‐1 gene. Most of the reported mutations are missense substitutions mainly affecting the epidermal growth factor (EGF)‐like protein domain structure and the calcium‐binding (cb) site. The aim of our study was to investigate the correlation between fibrillin‐1 frameshift mutations and the clinical phenotype in patients affected by MFS. In 48 out of 66 Marfan patients a pathogenetic mutation was found. We detected novel mutations causing premature termination codon in exons 19, 37, 40 and 41 of four Italian patients. The first mutation in exon 19 (cbEGF #8 domain) results in a clinical phenotype involving mainly the skeletal and cardiovascular systems. Interestingly, we noticed that, while mutations in exons 37 and 41 (eight cysteine domains #4 and #5) are milder, the mutation in exon 40 (cbEGF #24 domain) is more severe and causes major cardiovascular involvement with thoracic and abdominal aortic aneurysms. It is noteworthy that the degree of the severity in the phenotype of one of our patients and another from the literature carrying a mutation in exon 41 could be explained with alterations in mRNA expression.
Both alleles of the M235T polymorphism of the angiotensinogen gene can be a risk factor for myocardial infarction
Authors: Fernández‐Arcás N , Dieguez‐Lucena JL , Muñoz‐Morán E , Ruiz‐Galdón M , Espinosa‐Caliani S , Aranda‐Lara P , Rius‐Diaz F , Gaitán‐Arroyo MJ , De Teresa‐Galván E , Reyes‐Engel A
Published: March 2003

We have studied the role of three polymorphic genes of the renin‐angiotensin system (RAS) as independent risk factors for myocardial infarction (MI) and their correlation with three of the major coronary risk factors: serum cholesterol (CH), hypertension (HT) and smoking (SM). A population of 392 men was genotyped for the M235T polymorphism of the angiotensinogen (AGT) gene, the insertion/deletion of the angiotensin‐converting enzyme (ACE) and the all66c of the angiotensin‐II type 1 receptor (AT1R), by means of polymerase chain reaction (PCR) and restriction enzyme analysis. It was observed that the T allele frequency increased significantly in the MI with HT, CH, and SM subgroup (0.58 vs 0.31) (p<0.01). In contrast, the M allele frequency was higher in the MI without HT, CH, and SM (0.69 vs 0.42) (p<0.01). A strong association between the MM genotype and MI (p<0.001, odds ratio=4.29, confidence interval=1.95–9.42) was found when age‐matched MM control subjects were compared to MI individuals with none of the other known major coronary risk factors. Futhermore, subjects with the MM genotype showed a significantly higher plasma renin activity (PRA) profile than those with the TT genotype (p<0.001). It can be concluded that the M allele is an independent risk factor for MI and the T allele modified the risk when other major risk factors are present.
Further evidence for linkage of low–mid frequency hearing impairment to the candidate region on chromosome 4p16.3
Authors: Brodwolf S , Böddeker IR , Ziegler A , Rausch P , Kunz J
Published: March 2003

We have investigated a three‐generation family with an autosomal dominant low–mid frequency hearing loss. Audiograms show consistently a hearing threshold of 50±20 db hearing loss (HL) between 250 Hz and 1–2 kHz. Normal hearing level was reached between 3 and 6 kHz in all examined children. Adult patients show an additional hearing impairment (HI) in the mid and higher frequencies that seems to differ from presbyacusis. The HI is always bilateral and symmetrical. Genes causing non‐syndromic autosomal‐dominant deafness with HI in the low and mid frequencies were previously mapped to chromosome 4p16.3 (DFNA6, DFNA14) and chromosome 5q31 (DFNA1). After exclusion of linkage to DFNA1 on chromosome 5, we mapped the candidate gene region to the DFNA14 and DFNA6 loci, between the genetic markers D4S432 and D4S431, located on chromosome 4. This is a further family in which evident linkage of low–mid frequency HI to the candidate region on chromosome 4p16.3 has been found.
Lack of association of the common TaqIB polymorphism in the cholesteryl ester transfer protein gene with angiographically assessed coronary atherosclerosis
Authors: Arca M , Montali A , Ombres D , Battiloro E , Campagna F , Ricci G , Verna R
Published: March 2003

The anti‐atherogenic effect of cholesteryl ester transfer protein (CETP) genetic variants associated with lowered enzyme activity is controversial. Moreover, in a few studies, this effect has been evaluated in the presence of a certain risk factor constellation. We addressed this issue in a case–control study, where 415 subjects with angiographically documented coronary artery disease (CAD+), 397 subjects without CAD (in 215, CAD was excluded by coronarography (CAD−)), and 188 healthy population controls, were screened for the CETP TaqIB polymorphism. The prevalence of the low‐activity TaqIB2 allele was 0.396 in CAD+, and 0.428 and 0.416 in CAD− and population controls, respectively (p=0.40). Its presence was significantly associated with increased high‐density lipoprotein cholesterol (HDL‐C) in population controls (1.40±0.40 mmol/l in B1B1, 1.52±0.39 mmol/l in B1B2 and 1.58±0.46 mmol/l in B2B2; p<0.03 for trend), but not in the other groups. The CETP TaqIB polymorphism accounted for <1% of the HDL‐C variance in the whole cohort (p=0.048). After adjustment for other risk factors, the CETP TaqIB2 allele was found not to be associated with significant changes in CAD risk independently of an assumed either dominant (odds ratio (OR) 0.97; 95% confidence interval (CI) 0.66–1.44; p=0.89) or recessive effect (OR 0.68; 95% CI 0.42–1.12; p=0.13). The CETP TaqIB polymorphism did not show a significant interaction with other risk factors in influencing CAD risk. Our findings do not support the hypothesis that a genetic variant resulting in lowered CETP activity is associated with reduced risk of coronary atherosclerosis.
A family with a grand‐maternally derived interstitial duplication of proximal 15q
Authors: Boyar FZ , Whitney MM , Lossie AC , Gray BA , Keller KL , Stalker HJ , Zori RT , Geffken G , Mutch J , Edge PJ , Voeller KS , Williams CA , Driscoll DJ
Published: March 2003

About 1% of individuals with autism or types of pervasive developmental disorder have a duplication of the 15q11‐q13 region. These abnormalities can be detected by routine G‐banded chromosome study, showing an extra marker chromosome, or demonstrated by fluorescence in situ hybridization (FISH) analysis, revealing an interstitial duplication. We report here the molecular, cytogenetic, clinical and neuropsychiatric evaluations of a family in whom 3 of 4 siblings inherited an interstitial duplication of 15q11‐q13. This duplication was inherited from their mother who also had a maternally derived duplication. Affected family members had apraxia of speech, phonological awareness deficits, developmental language disorder, dyslexia, as well as limb apraxia but did not have any dysmorphic clinical features. The observations in this family suggest that the phenotypic manifestations of proximal 15q duplications may also involve language‐based learning disabilities.
ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels
Authors: Zwarts KY , Clee SM , Zwinderman AH , Engert JC , Singaraja R , Loubser O , James E , Roomp K , Hudson TJ , Jukema JW , Kastelein JJP , Hayden MR
Published: March 2003

The authors have previously shown that individuals heterozygous for ABCA1 mutations have decreased high density lipoprotein cholesterol, increased triglycerides and an increased frequency of coronary artery disease (CAD), and that single nucleotide polymorphisms (SNPs) in the coding region of the ABCA1 gene significantly impact plasma lipid levels and the severity of CAD in the general population. They have now identified several SNPs in non‐coding regions of ABCA1 which may be important for the appropriate regulation of ABCA1 expression (i.e. in the promoter, intron 1 and the 5′ untranslated region), and have examined the phenotypic effects of these SNPs in the REGRESS population. Out of 12 SNPs, four were associated with a clinical outcome. A threefold increase in coronary events with an increased family history of CAD was evident for the G‐191C variant. Similarly, the C69T SNP was associated with a twofold increase in events. In contrast, the C‐17G was associated with a decrease in coronary events and the InsG319 was associated with less atherosclerosis. For all these SNPs, the changes in atherosclerosis and CAD occurred without detectable changes in plasma lipid levels. These data suggest that common variation in non‐coding regions of ABCA1 may significantly alter the severity of atherosclerosis, without necessarily influencing plasma lipid levels.
A low prevalence of the C677T mutation in the methylenetetrahydrofolate reductase gene in Asian Indians
Authors: Mukherjee M , Joshi S , Bagadi S , Dalvi M , Rao A , Shetty KR
Published: March 2003

The prevalence of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in Asian Indians from India was determined and the association of the mutant allele with coronary artery disease (CAD) was evaluated in a case–control study. The case group consisted of 251 patients with CAD; 195 male and 56 female aged from 29 to 82 years (mean age ± SD, 57.5 ± 10.6 years). The control group consisted of 216 apparently healthy individuals without evidence of CAD; 161 male and 55 female aged from 30 to 83 years (mean age ± SD, 54.9 ± 10.4 years). All the patients were assessed by coronary angiography. While 33 patients had normal coronaries, 23, 25 and 39 patients had single‐vessel, two‐vessel and triple‐vessel disease, respectively. Eighty‐three patients (33%) had suffered myocardial infarction less than a year to five years earlier. The C677T polymorphism in the MTHFR gene was assessed. While 31% of the controls and 38% of the patients had the heterozygous genotype, 2% of the control group and none of the patients had the mutant homozygous genotype. The overall ‘T’ allelic frequencies were comparable in control and patient groups (0.18 and 0.19, respectively), but the association of the sum of heterozygous and homozygous genotypes with CAD (1, 2 or 3‐vessel disease) was statistically significant for females only [Odds ratio (95% confidence intervals), 2.8 (1.1–6.9), p = 0.023]. No association was found between genotype distribution and previous myocardial infarction or severity of atherosclerosis.