Biomedical subjects

J Weissenbach

Publications and source records attributed to J Weissenbach.

At least 181 records · Page 10Linked to original sources

PubMed1995

Haplotype analysis in gelsolin-related amyloidosis reveals independent origin of identical mutation (G654A) of gelsolin in Finland and Japan.

Familial amyloidosis, Finnish type (FAF) (gelsolin-related amyloidosis) is an autosomal dominant form of systemic amyloidosis characterized by corneal lattice dystrophy and peripheral polyneuropathy. The accumulating protein in FAF consists of fragments of gelsolin, an actin-modulating protein. The gelsolin mutation G654A has been found in both Finnish and Japanese patients. To study the origin of the gelsolin mutation in these patients we performed haplotype analysis in 10 Finnish and 2 Japanese FAF families. Poymorphic DNA markers GSN, D9S103, AFMa061xd9, and AFMa139xb9 revealed a uniform disease haplotype in all the disease-associated chromosomes of the Finnish FAF families, which was different from the one observed in the Japanese families. The present results and the previously detected gelsolin mutation G654T in Czech and Danish FAF patients suggest that nucleotide 654 may represent a mutation hot spot in the gelsolin gene. The DNA markers studied here will be useful in future genealogical analyses of FAF.

Amyloid Neuropathies↗

PubMed1995

Exclusion of the cone-specific alpha-subunit of the transducin gene in Stargardt's disease.

Stargardt's disease is an autosomal recessive infantile macular degeneration of unknown origin whose gene has been recently mapped to chromosome 1p21-p13 by linkage analysis in eight multiplex families. Since the cone-specific alpha-subunit of the transducin gene (GNAT2) has been mapped to chromosome 1p13, we tested GNAT2 as the disease-causing gene in our series. Using a novel intragenic polymorphism, we show here that GNAT2 is most probably located centromeric to the genetic interval encompassing the disease gene (D1S424-D1S236, location score = 3.54). In addition, single-strand conformation polymorphism and sequence analyses of the eight exons of the GNAT2 gene was performed in our probands. No evidence of a deleterious base substitution was observed in any affected individual. Taken together, these results support the exclusion of GNAT2 as the causal disease gene of Stargardt's disease. come. The pathogenesis is unknown and the treatment is limited to ultraviolet ray protection with dark glasses. Stargardt's disease has been recently mapped to chromosome 1p21-p13 in the genetic interval defined by loci D1S424 and D1S236. In addition, our previous study has suggested that Stargardt's disease is genetically homogeneous (Kaplan et al. 1993). With respect to the physical mapping of the proteins specific to the retinal pigmentary epithelium or to cones we noted that the cone-specific alpha-subunit of the transducin gene (GNAT2) has been mapped to chromosome 1p13 (Wilkie et al. 1992). The human GNAT2 is 9967 bp in length and consists of eight exons with seven introns (Morris and Fong 1993). In the present study, we examined this gene as the candidate gene in eighteen unrelated patients affected with Stargardt's disease.

Base Sequence↗

PubMed1995

A high-density microsatellite map of the ataxia-telangiectasia locus.

The locus of the autosomal recessive disorder ataxia-telangiectasia (A-T) has been assigned by linkage analysis with biallelic markers to a 4-Mb interval on chromosome 11q22-23, between GRIA4 and D11S1897. We have undertaken to saturate the A-T region with highly polymorphic microsatellite markers. To this end, we have identified seven new polymorphic CA-repeats in this region, and have mapped to it five new markers generated by Genethon and the Cooperative Human Linkage Center. These markers are in addition to 12 others that we have previously mapped or generated at the A-T locus. All 24 markers have been integrated into a high-density microsatellite map spanning some 6 Mb DNA. This map, which contains the A-T locus and flanking sequences, allows the construction of extensive, highly informative haplotypes.

Ataxia Telangiectasia↗

PubMed1995

No evidence of genetic heterogeneity in Crouzon craniofacial dysostosis.

Crouzon craniofacial dysostosis (CFD) is an autosomal dominant form of craniosynostosis characterized by an abnormal skull shape, with hypertelorism, prominent eyes and midfacial retrusion. Recently, a gene for CFD has been mapped to chromosome 10q25-q26 and mutations in exon B of the fibroblast growth factor receptor 2 (FGFR2) gene have been identified. Here, we report the mapping of a CFD gene to chromosome 10q by close linkage to probe AFMa197wb1 at locus D10 S1483 in six unrelated families of French ancestry (Zmax = 4.69 at theta = 0) and provide additional evidence of genetic homogeneity of this condition. In addition, we report a novel mutation in exon B of the FGFR2 gene (Cys 342 Trp) in familial CFD and describe recurrent mutations at codon 342 as a particularly frequent event in CFD. Since mutations in the extracellular domain of the FGFR2 gene are observed in a few clinically distinct craniosynostosis syndromes (CFD, Jackson-Weiss, Apert and Pfeiffer), the present study gives support to the variable clinical expression of FGFR2 mutations in humans.

Chromosome Mapping↗

PubMed1995

Establishment of the marker order pter-NRAS-NGFB-D1S189-D1S252-D1S440-D1S453-D1S514-CEN-D1S442-D1S498-qte r in relation to the centromere on human chromosome 1.

Recent developments in genetic linkage mapping of the human genome have generated a large number of short tandem repeat polymorphic markers (Weissenbach et al. 1992, Gyapay et al. 1994), and eventual integration of these markers into a physical map is a logical progression. A number of Généthon microsatellite (CA repeat) markers have been provisionally localized to 1p13, but their exact position with respect to other sequences is unknown. In order to confirm the order of these markers and their position with respect to known genes within 1p13 and the centromere, we have isolated yeast artificial chromosomes (YACs) corresponding to the markers and have carried out double and triple fluorescence in situ hybridization (FISH) studies. Knowledge of both the order of microsatellite markers and their integration with a physical map of known genes can be an essential component in analysis of disease loci such as human cancer, where regions of chromosomes showing high levels of loss of heterozygosity need to be mapped in detail.

Centromere↗

PubMed1995

Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13.

Loss of heterozygosity (LOH) on chromosome 13 occurs on 25-30% of breast tumours. This may reflect the inactivation of the retinoblastoma susceptibility gene RB1. However, recently another candidate tumour-suppressor gene has been identified on chromosome 13 by linkage analysis, the breast cancer susceptibility gene BRCA2. To investigate the involvement of BRCA2 in sporadic breast cancer 200 breast tumours were tested for LOH on chromosome band 13q12-q14, using 11 highly polymorphic microsatellite markers. LOH was found in 65 tumours, which all showed simultaneously loss of BRCA2 and RB1. Of 12 breast tumour cell lines tested with polymorphic microsatellite markers, seven showed a contiguous region of homozygosity on 13q12-q14, suggesting LOH in the tumour from which the cell line had been derived. One cell line showed homozygosity in the BRCA2 region and heterozygosity at RB1. This is the only indication that BRCA2 is a distinct target for LOH on chromosome 13 in addition to RB1.

Alleles↗

PubMed1995

An autosomal locus predisposing to deletions of mitochondrial DNA.

The molecular mechanisms by which the nuclear genome regulates the biosynthesis of mitochondrial DNA (mtDNA) are only beginning to be unravelled. A naturally occurring in vivo model for a defect in this cross-talk of two physically separate genomes is a human disease, an autosomal dominant progressive external ophthalmoplegia, in which multiple deletions of mtDNA accumulate in the patients' tissues. The assignment of this disease locus to 10q 23.3-24.3 is the first direct evidence for involvement of both nuclear and mitochondrial genomes in a single disorder.

Base Sequence↗

PubMed1995

The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24.

Autosomal recessive Meckel syndrome (OMIM 249000) (MES), first described in 1822 by Johann F. Meckel, is a major monogenic malformation syndrome with a neural tube defect leading to death of the fetus in utero or shortly after birth. The hallmarks of the syndrome are occipital meningoencephalocele, very large kidneys with multicystic dysplasia, cystic and fibrotic changes of the liver and polydactyly (Fig. 1). Other typical malformations for MES are cleft lip and palate, urinary tract anomalies, ambiguous genitals in the males and club feet. Although MES has been reported worldwide, reports on the true birth prevalence of MES in different populations are scarce. In Finland MES is effectively screened and relatively frequent with a birth prevalence of 1:9,000 and a disease gene frequency of 0.01 (ref.4) which is of the same order of magnitude as that of the most common recessive diseases belonging to the 'Finnish disease heritage', that is genetic disorders enriched or only encountered in Finland. However, in MES, comparable or even higher incidences are also reported from other populations. Here, we report the assignment of the MES locus to chromosome 17q21-q24 in the 13 cM region, and exclude some of the potential candidate genes located in this critical chromosomal region.

Abnormalities, Multiple↗

PubMed1995

Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy.

Congenital muscular dystrophies (CMDs), are heterogeneous autosomal recessive disorders. Their severe manifestations consist of early hypotonia and weakness, markedly delayed motor milestones and contractures, often associated with joint deformities. Histological changes seen in muscle biopsies consist of large variations in muscle fibre size, a few necrotic and regenerating fibres and a marked increase in endomysial collagen tissue. Diagnosis is based on clinical features and on morphological changes. In several CMD cases, we have demonstrated an absence of one of the components of the extracellular matrix around muscle fibres, the merosin M chain, now referred to as the alpha 2 chain of laminin-2 (ref.3). We localized this CMD locus to chromosome 6q2 by homozygosity mapping and linkage analysis. The laminin alpha 2 chain gene (LAMA2) maps to the same region on chromosome 6q22-23 (ref. 5). We therefore investigated LAMA2 for the presence of disease-causing mutations in laminin alpha 2 chain-deficient CMD families and now report splice site and nonsense mutations in two families leading presumably to a truncated laminin alpha 2 protein.

Adult↗

PubMed1995

Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.

Amino Acid Sequence↗

PubMed1995

An integrated physical and genetic map of a 35 Mb region on chromosome Xp22.3-Xp21.3.

We have constructed a detailed physical map of the 35 Mb region spanning human chromosome Xp22.3-Xp21.3. The backbone of the map is represented by a single oriented contiguous stretch of 585 overlapping yeast artificial chromosome (YAC) clones covering the entire region. The map is formatted with 615 map objects that include 324 YACs, 185 sequence tagged sites, 28 genes, 85 chromosomal breakpoints and 37 highly polymorphic markers. Physical mapping was both guided and confirmed using 183 bins defined by chromosomal breakpoints and by overlapping regions of YAC clones. The localization of polymorphic markers in the physical map permits the integration of physical and genetic data across the region. These data establish chromosome Xp22.3-Xp21.3 as one of the best characterized large regions in the human genome. The map should greatly facilitate finer scale mapping and sequencing as well as the identification of disease genes from this portion of the human genome.

Base Sequence↗

PubMed1995

The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy which presents typically after the age of 50 with progressive eyelid drooping and an increasing difficulty in swallowing. Though OPMD has a world-wide incidence, it is more common in the French Canadian population. We have identified a homogeneous group of families and studied 166 polymorphic markers as part of a genome search before establishing linkage to chromosome 14. We determined that the OPMD locus maps to a less than 5 cM region of chromosome 14q11.2-q13. The maximum two-point lod score in three French Canadian families of 14.73 (theta = 0.03) was obtained for an intronic cardiac beta myosin heavy chain gene (MYH7) marker. The regional localization for the OPMD locus raises the intriguing possibility that either the cardiac alpha or beta myosin heavy chain genes may play a role in this disease.

Base Sequence↗

PubMed1995

Three genes that escape X chromosome inactivation are clustered within a 6 Mb YAC contig and STS map in Xp11.21-p11.22.

In order to study the distribution of genes that escape X chromosome inactivation, a high density yeast artificial chromosome (YAC) contig and STS map spanning approximately 6 Mb has been constructed in Xp11.21-p11.22. The contig contains 113 YACs mapped with 53 markers, including 10 genes. Four genes have been assayed for their expression status on both the active and inactive human X chromosomes, and these data have been combined with previous results on two other genes in the contig. Three of these genes escape X inactivation and have been localized to a single YAC clone of approximately 1075 kb. The other three genes are subject to inactivation, with two of them lying among the genes that escape inactivation. These results suggest that there are both regional control signals as well as gene-specific elements that determine the X inactivation status of genes on the proximal short arm of the human X chromosome.

Base Sequence↗

PubMed1995

A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q.

Hereditary haemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomal dominant vascular disorder which associates epistaxis, mucocutaneous and visceral telangiectases, and recurrent haemorrhage with chronic anaemia and visceral shuntings. Recently, the tumour growth factor (TGF)-beta binding protein endoglin localized to 9q33-34 was identified as responsible for HHT in several large kindreds with pulmonary arteriovenous malformations (PAVMs). Additional linkage studies demonstrated that HHT is a genetically heterogeneous disorder with families unlinked to this region of 9q. In the families in which HHT was not linked to chromosome 9, less PAVMs were present. Furthermore, in one of these families, HHT was found linked to 3p22, where the TGF-beta II receptor is located. In this linkage study, we have analysed DNA from two families, in which HHT was unlinked to chromosome 9q and 3p, and PAVMs were absent, with a series of genetic markers on the centromeric region of chromosome 12. Using two-point linkage analysis, a significant lod score of Zmax = 7.86 at theta = 0.05 was obtained with the D12S85 microsatellite marker.

Antigens, CD↗

PubMed1995

Genetic and physical characterization of the early-onset Alzheimer's disease AD3 locus on chromosome 14q24.3.

Genetic linkage studies have provided significant evidence that a major gene defect, AD3, for familial early-onset Alzheimer's disease (EOAD) is located at chromosome 14q24.3, between the short tandem repeat (STR) markers D14S52 and D14S53 defining a genetic size of 22.7 cM for the AD3 candidate region. We constructed a physical map of the AD3 region using yeast artificial chromosomes (YACs) selected from both the CEPH and megaCEPH YAC libraries using the AD3 linked STR markers as well as new sequence-tagged sites (STSs) designed based on YAC terminal sequences. The YAC map is contiguous in the region between D14S258 and D14S53, a region of 8.2 cM, and has an estimated physical size of 4-8 Mb. The YAC contig map was used as a framework to localize three known genes, a pseudogene and two brain expressed sequence tags (ESTs). Linkage analysis studies in two Belgian chromosome 14 EOAD families AD/A and AD/B, identified obligate recombinants in family AD/A with D14S289 and D14S61 reducing the genetic size of the candidate AD3 region substantially. The minimal AD3 candidate region measured 6.4 cM on the genetic map and is contained within six overlapping megaCEPH YACs that covered a physical distance estimated between 2 and 6 Mb. These YACs as well as other YACs in the YAC contig map are valuable resources in gene cloning efforts or genomic sequencing experiments aiming at isolating the AD3 gene.

Age of Onset↗

PubMed1995

Autosomal recessive lamellar ichthyosis: identification of a new mutation in transglutaminase 1 and evidence for genetic heterogeneity.

Autosomal recessive lamellar ichthyosis (ARLI) belongs to the group of congenital disorders of cornification. It is characterized by a severe and generalized ichthyosis, and other variable cutaneous signs. The human transglutaminase 1 (TGM1) gene was recently found to be the disease-causing gene. Linkage analysis in 23 families (of which 13 were consanguineous) showed that for 10 of them, the disease was linked to the TGM1 gene. A new deleterious mutation introducing a stop codon in the TGM1 reading frame was found. Nevertheless, for the 13 other ARLI families, TGM1 was found to be unlinked to the disease. The present data show that ARLI is genetically heterogeneous and confirm that TGM1 is one of the responsible genes.

Base Sequence↗

PubMed1995

Localization of the Schwartz-Jampel syndrome (SJS) locus to chromosome 1p34-p36.1 by homozygosity mapping.

Schwartz-Jampel syndrome (SJS, MIM 255800), also known as chondrodystrophic myotonia, is a rare autosomal recessive disorder characterized by generalized myotonia, skeletal abnormalities and facial dysmorphism. Using homozygosity mapping, we localized the SJS locus to chromosome 1p34-p36.1 in a 8 cM interval flanked by markers D1S199 and D1S234. Families of different ethnic backgrounds (Tunisia and South Africa) showed genetic linkage to the same locus. Moreover, one Algerian family also demonstrated evidence of genetic linkage to 1p34-p36.1. Taken altogether, our results suggest genetic homogeneity, at least in the group of families analyzed.

Chromosome Mapping↗

PubMed1995

The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7.

The recently identified mouse obese (ob) gene apparently encodes a secreted protein that may function in the signaling pathway of adipose tissue. Mutations in the mouse ob gene are associated with the early development of gross obesity. A detailed knowledge concerning the RNA expression pattern and precise genomic location of the human homolog, the OB gene, would facilitate examination of the role of this gene in the inheritance of human obesity. Northern blot analysis revealed that OB RNA is present at a high level in adipose tissue but at much lower levels in placenta and heart. OB RNA is undetectable in a wide range of other tissues. Comparative mapping of mouse and human DNA indicated that the ob gene is located within a region of mouse chromosome 6 that is homologous to a portion of human chromosome 7q. We mapped the human OB gene on a yeast artificial chromosome (YAC) contig from chromosome 7q31.3 that contains 43 clones and 19 sequence-tagged sites (STSs). Among the 19 STSs are eight corresponding to microsatellite-type genetic markers, including seven (CA)n repeat-type Genethon markers. Because of their close physical proximity to the human OB gene, these eight genetic markers represent valuable tools for analyzing families with evidence of hereditary obesity and for investigating the possible association between OB mutations and human obesity.

Adipose Tissue↗