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J Weissenbach

Publications and source records attributed to J Weissenbach.

At least 199 records · Page 11Linked to original sources
PubMed1995

Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.

Cerebral cavernous malformations (CCM) are vascular lesions present in some 20 million people worldwide that are responsible for seizures, migraine, hemorrhage, and other neurologic problems. Familial cases ofCCM can be inherited as an autosomal dominant disorder with variable expression. A gene for CCM (CCM/)was recently mapped to a 33-cM segment of chromosome 7q in a large Hispanic family (Dubovsky et al.1995). Here, the collection of several new short tandem repeat polymorphisms (STRPs) within the region of interest on 7q and the refinement of the marker order in this region using both linkage analysis in CEPH families and especially YAC-based STS content mapping are described. Affected members of three Hispanic families share allele haplotypes indicating a common ancestral mutation within these families. Using the shared haplotype information along with analysis of crossovers in affected individuals from both the Hispanic and Caucasian families, the region likely to contain the CCMI gene has been reduced to a 4-cM segment of 7q between D7S2410 and D7S689. All markers within the refined chromosomal segment were located on a single YAC contig estimated to be approximately 2 Mb in size. Four potential candidate genes have been mapped to this region.

Base Sequence↗
PubMed1995

Integrated genetic map of human chromosome 2.

A framework genetic map of human chromosome 2 is described, integrating data from the Centre d'Etude du Polymorphisme Humain (CEPH) version 6 database, the CEPH chromosome 2 consortium database, the National Institute of Health (NIH)/CEPH Collaborative Mapping group and other laboratories. A comprehensive map is also presented, showing regional locations of a large number of additional loci. The framework map is used to identify an informative set of meiotic breakpoints within the CEPH families, and the utility of this information for mapping new markers is discussed. The degree of typing error within the data set is estimated, as are the sex-specific interference parameters. A location database for these genetic and additional cytogenetic data is constructed using algorithms which map genetic distances on to a physical scale, and the potential for this approach to aid the integration of genetic and physical data is examined.

Chromosome Mapping↗
PubMed1995

No evidence of genetic heterogeneity in dominant optic atrophy.

Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease causing a variable reduction of visual acuity with an insidious onset in the first six years of life. It is associated with a central scotoma and an acquired blue-yellow dyschromatopsia. A gene for dominant optic atrophy (OPA1) has recently been mapped to chromosome 3q in three large Danish pedigrees. Here, we confirm the mapping of OPA1 to chromosome 3q28-qter by showing close linkage of the disease locus to three recently reported microsatellite DNA markers in the interval defined by loci D3S1314 and D3S1265 in four French families (Zmax = 5.13 at theta = 0 for probe AFM 308yf1 at locus D3S1601). Multipoint analysis supports the mapping of the disease gene to the genetic interval defined by loci D3S1314 and D3S1265. The present study provides three new markers closely linked to the disease gene for future genetic studies in OPA.

Chromosome Mapping↗
PubMed1995

Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome.

Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Confirmation of genetic heterogeneity in familial psoriasis.

Psoriasis affects approximately 2% of the European population and is often familial. Linkage of a subset of psoriasis families to loci on chromosome 17q has recently been reported. We have studied members of a large multiply affected family from the north east of England and analysed genotypes for markers from 17q, including the polymorphic microsatellite markers AFM210xa5, AFM163yg1, AFM044xg3, AFMa353yg1, and AFM217yd19. Two point and multipoint analysis clearly show exclusion of linkage between the telomeric region of 17q and psoriasis in this family. This confirms the genetic heterogeneity of psoriasis and the existence of at least one other major psoriasis locus.

Chromosomes, Human, Pair 17↗
PubMed1995

An isolated cardiac conduction disease maps to chromosome 19q.

Isolated cardiac conduction disease is an autosomal dominant defect that includes various combinations of bundle branch or fascicular blocks. These defects can cause sudden death due to a complete heart block. We used a genome-wide screening approach with polymorphic (CA)n repeat markers to determine the chromosomal position of the gene defect implicated in this disorder. The analyses were carried out on a large Lebanese kindred, which included individuals with either a complete or incomplete right bundle branch block (RBBB) with a vertical-axis deviation (< or = -30 or > or = +100). Linkage to the disease locus was detected with the polymorphic marker D19S604 on the q arm of chromosome 19 (19q13.3) with a multipoint lod score of 7.18. Additionally, we were able to exclude the flanking loci D19S606 and D19S571, which are 13 cM apart because of recombination events in three affected individuals. The histidine-rich calcium-binding protein gene is found in this region and is an attractive candidate gene on the basis of its physiological properties and a tight linkage. There is no expansion in two exon 1 regions known for a variable number of triplet repeats.

Base Sequence↗
PubMed1995

Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14.

Miyoshi myopathy (MM) is a young-adult-onset, autosomal recessive distal muscular dystrophy initially affecting the plantar flexors. We analyzed 12 MM families, five with consanguineous marriage, for chromosomal linkage using polymorphic microsatellite DNA markers to map the MM gene. A significant lod score was obtained with the 2p12-14 locus D2S291 (Zmax = 15.3 at theta = 0). Two additional 2p12-14 markers, D2S286 (Z = 10.7 at theta = 0) and D2S292 (Z = 7.2 at theta = 0.05), also gave significant lod scores. These markers will be useful for diagnosis of symptomatic and presymptomatic patients, prenatal and carrier diagnosis of family members carrying MM, and ultimately identification of a gene responsible for MM.

Adolescent↗
PubMed1995

Selective intestinal malabsorption of vitamin B12 displays recessive mendelian inheritance: assignment of a locus to chromosome 10 by linkage.

Juvenile megaloblastic anemia caused by selective intestinal malabsorption of vitamin B12 has been considered a distinct condition displaying autosomal recessive inheritance. It appears to have a worldwide distribution, and comparatively high incidences were reported 30 years ago in Finland and Norway. More recently, the Mendelian inheritance of the condition has been questioned because almost no new cases have occurred in these populations. Here we report linkage studies assigning a recessive-gene locus for the disease to chromosome 10 in previously diagnosed multiplex families from Finland and Norway, proving the Mendelian mode of inheritance. The locus is tentatively assigned to the 6-cM interval between markers D10S548 and D10S466, with a multipoint maximum lod score (Zmax) of 5.36 near marker D10S1477. By haplotype analysis, the healthy sibs in these families did not appear to constitute any examples of nonpenetrance. We hypothesize that the paucity of new cases in these populations is due either to a dietary effect on the gene penetrance that has changed with time, or to a drop in the birth rate in subpopulations showing enrichment of the mutation, or to both of these causes.

Adolescent↗
PubMed1995

Lysosomal free sialic acid storage disorders with different phenotypic presentations--infantile-form sialic acid storage disease and Salla disease--represent allelic disorders on 6q14-15.

Similarities in biochemical findings have suggested that Salla disease (SD) and the infantile form of sialic acid storage disease (ISSD) could represent allelic disorders, despite their drastically different clinical phenotypes. SD and ISSD are both characterized by lysosomal storage of free N-acetyl neuraminic acid. However, in SD the increase detected in urine is 8-24-fold, whereas in ISSD the corresponding amount is 20-50-fold and patients are also more severely affected. Here we report linkage studies in 50 Finnish SD families and 26 non-Finnish families with no genealogical connections to Finns affected either with the Finnish type of SD, the "intermediate" form of the disease, or ISSD. All forms of the disease show linkage to the same locus on 6q14-q15. Haplotype analyses of Finnish SD chromosomes revealed one common haplotype, which was also seen in most of the non-Finnish patients with Finnish type of SD. This ancestral haplotype deviated from those observed in ISSD patients, who had a different common haplotype.

Alleles↗
PubMed1995

Readjusting the localization of long QT syndrome gene on chromosome 11p15.

Long QT syndrome (LQT) is an autosomal dominant cardiac disease characterized by ventricular arrhythmia. A first locus for LQT has been identified on chromosome 11p15.5 (LQT1), closely linked to HRAS. To refine the location of LQT1, microsatellites were genotyped in 8 French families and the following order was determined: tel-HRAS-DRD4-D11S922-D11S4046- IGF2-INS-TH-D11S1318-D11S1323-D11S1338-D11S90 9-D11S1346-cen. By haplotype analysis, 12 crossing-over events were identified in affected and unaffected subjects, delineating the LQT1 candidate region to 7 cM. This new delineated localization between D11S1318 and D11S1323 is in a more centromeric region than previously thought and is 5 cM proximal to HRAS.

Chromosome Mapping↗
PubMed1995

[Gene localisation in 12q12 in Holt-Oram atrio-digital syndrome].

The Holt-Oram syndrome, first described in 1960, consists of non-cyanotic congenital heart disease, usually an atrial septal defect, arrhythmias and malformations of the upper limbs affecting the radial segment. The transmission of the syndrome is autosomal dominant with almost complete penetrance. The authors report the localisation of a genetic abnormality of the Holt-Oram syndrome on the long arm of chromosome 12 (12q21-q3) by analysis of linkage in 9 multiplex families (Zmax = 8.19 at locus D12S354). Multipoint analysis showed a genetic interval of 7 centimorgans containing a gene of the Holt-Oram syndrome between loci D12S84 and D12S79 (multipoint lod score, 10 g base 10 = 8.96). In situ hybridization of artificial yeast chromosomes containing the surrounding markers showed that a gene of the Holt-Oram syndrome is located in 12q23-q24. The genetic heterogeneity was demonstrated in 3 families of the Holt-Oram syndrome with polydactyly or without cardiac disease (homog-test: chi 2 = 13.28; p = 0.0001). The localisation of a gene of the Holt-Oram syndrome is, to the authors' knowledge, the first chromosomal localisation of a cardiac malformation with septal defects in man. The identification of this gene should open wide perspectives for genetic research of cardiac morphogenesis and clarify the molecular mechanisms which govern cardiac septation during embryogenesis.

Chromosome Mapping↗
PubMed1995

Chromosome 9p deletions in cutaneous malignant melanoma tumors: the minimal deleted region involves markers outside the p16 (CDKN2) gene.

We have analyzed 12 microsatellite markers on chromosome 9p in 54 paired cutaneous malignant melanoma (CMM) tumors and normal tissues. Forty-six percent of the tumors, including two in situ CMMs, showed loss of heterozygosity (LOH) at 9p. Only one tumor was homozygously deleted for 9p markers. The smallest deleted region was defined by five tumors and included markers D9S126 to D9S259. Loss of eight or more markers correlated significantly with worse prognosis (P < .002). Among the primary tumors, 87.5% of those with large deletions have a high risk of metastasis, as compared with only 18% of those without deletions or with loss of fewer than 8 markers (P < .001). It was not possible to demonstrate homozygous deletions of p16 in any of the CMM tumors. In four tumors, the LOH for 9p markers did not involve p16. The reported data suggest the existence of several tumor suppressor genes at 9p that are involved in the predisposition to and/or progression of CMM and exclude p16 from involvement in the early development of some melanoma tumors.

Base Sequence↗
PubMed1995

Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus.

Infantile-onset spinocerebellar ataxia (IOSCA) is an autosomal recessively inherited progressive neurological disorder of unknown etiology. This ataxia, identified so far only in the genetically isolated Finnish population, does not share gene locus with any of the previously identified hereditary ataxias, and a random mapping approach was adopted to assign the IOSCA locus. Based on the assumption of one founder mutation, a primary screening of the genome was performed using samples from just four affected individuals in two consanguineous pedigrees. The identification of a shared chromosomal region in these four patients provided the first evidence that the IOSCA gene locus is on chromosome 10q23.3-q24.1, which was confirmed by conventional linkage analysis in the complete family material. Strong linkage disequilibrium observed between IOSCA and the linked markers was utilized to define accurately the critical chromosomal region. The results showed the power of linkage disequilibrium in the locus assignment of diseases with very limited family materials.

Age of Onset↗
PubMed1995

Ataxia with vitamin E deficiency: refinement of genetic localization and analysis of linkage disequilibrium by using new markers in 14 families.

Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disease characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich ataxia. This disorder has been reported previously as familial isolated vitamin E deficiency. We have mapped recently the AVED locus to a 5-cM confidence interval on chromosome 8q by homozygosity mapping in six Mediterranean families. We have now analyzed six new and two previously described families and demonstrate genetic homogeneity despite important clinical variability and wide geographic origins. Analysis of nine new tightly linked microsatellite markers, including four characterized in this study, revealed a predominant but not unique mutation in northern African populations, where this condition is more frequent. Haplotype analysis but also classical recombinations allowed us to refine the AVED position to a 1-cM interval. A YAC contig over this interval was constructed from marker STSs and YAC fingerprint data, in order to facilitate the search of the AVED gene.

Africa, Northern↗
PubMed1995

A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q.

Primary open-angle glaucoma (POAG), which causes progressive loss of the visual fields, was subdivided into two groups according to age at onset: (1) chronic open-angle glaucoma (COAG) diagnosed after age 40 years and (2) juvenile open-angle glaucoma (JOAG) diagnosed between 3 years of age and early adulthood. A JOAG gene (GLC1A) was recently mapped to chromosome 1q. We studied 142 members of a huge multigenerational French Canadian family affected with autosomal dominant POAG. Either JOAG or COAG was diagnosed in 40 patients. Six subjects were also diagnosed with ocular hypertension (OHT), which may lead to POAG. To localize a common disease gene that might be responsible for both glaucoma subsets, we performed linkage analysis considering JOAG and COAG under the same phenotypic category. JOAG/COAG was tightly linked to seven microsatellite markers on chromosome 1q23-q25; a maximum lod score of 6.62 was obtained with AF-M278ye5. To refine the disease locus, we exploited a recombination mapping strategy based on a unique founder effect. The same characteristic haplotype, composed of 14 markers spanning 12 cM between loci D1S196 and D1S212, was recognized in all persons affected by JOAG, COAG, or OHT, but it did not occur in unaffected spouses and in normal family members > 35 years of age, except for three obligatory carriers. Key recombination events confined the disease region within a 9-cM interval between loci D1S445 and D1S416/D1S480. These observations demonstrate that the GLC1A gene is responsible for both adult-onset and juvenile glaucomas and suggest that the JOAG and COAG categories within this family may be part of a clinical continuum artificially divided at age 40 years.

Adolescent↗