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J Weissenbach

Publications and source records attributed to J Weissenbach.

At least 19 recordsLinked to original sources
PubMed1998

A physical map of 30,000 human genes.

A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping. The new gene map contains nearly twice as many genes as the previous release, includes most genes that encode proteins of known function, and is twofold to threefold more accurate than the previous version. A redesigned, more informative and functional World Wide Web site (www.ncbi.nlm.nih.gov/genemap) provides the mapping information and associated data and annotations. This resource constitutes an important infrastructure and tool for the study of complex genetic traits, the positional cloning of disease genes, the cross-referencing of mammalian genomes, and validated human transcribed sequences for large-scale studies of gene expression.

Animals↗
PubMed1998

New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study.

Rheumatoid arthritis (RA), the most common autoimmune disease, is associated in families with other autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). Its genetic component has been suggested by familial aggregation (lambdas = 5), twin studies, and segregation analysis. HLA, which is the only susceptibility locus known, has been estimated to account for one-third of this component. The aim of this paper was to identify new RA loci. A genome scan was performed with 114 European Caucasian RA sib pairs from 97 nuclear families. Linkage was significant only for HLA (P < 2.5.10(-5)) and nominal for 19 markers in 14 other regions (P < 0.05). Four of the loci implicated in IDDM potentially overlap with these regions: the putative IDDM6, IDDM9, IDDM13, and DXS998 loci. The first two of these candidate regions, defined in the RA genome scan by the markers D18S68-D18S61-D18S469 (18q22-23) and D3S1267 (3q13), respectively, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0. 001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA. Candidate genes include those coding for CD80 and CD86, molecules involved in antigen-specific T cell recognition. In conclusion, this first genome scan in RA Caucasian families revealed 14 candidate regions, one of which was supported further by the study of a second set of families.

Arthritis, Rheumatoid↗
PubMed1998

[Clinical and molecular genetic analysis of 4 Swiss families with the pure form of hereditary spastic spinal paralysis].

Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease of the spinal cord with a progressive gait disorder, associated with other neurological abnormalities in the complicated form. A cluster of families with this disorder in the central part of the country has long been known to Swiss neurologists. In the present report, we describe our clinical and molecular findings in four large families originating from this region and suffering from a pure HSP form. Clinical presentation was similar in the four families. The age of onset varied widely from 2 to 70 years with the appearance of a gait disorder, which slowly progressed to wheelchair confinement after 30-70 years. No other neurological abnormality was found except for impairment of the vibration sense and sphincter abnormalities. In three families an association with markers of the SPG4 locus on chromosome 2 was found. In the fourth, the largest one, no linkage could be found with either SPG4, or with the other two known loci, SPG3 on chromosome 14 and SPG6 on chromosome 15. These data demonstrate the genetic heterogeneity in HSP, even in families from the same region. They also suggest the presence of at least one additional locus for the pure form.

Adult↗
PubMed1998

A transcriptional Map of the FMF region.

Familial Mediterranean fever (FMF) is a recessively inherited disorder characterized by attacks of fever and serositis, which affects primarily non-Ashkenazi Jews, Armenians, Turks, and Arabs. We present here a transcriptional map covering the FMF locus that we constructed in the course of the positional cloning of the gene responsible for this disease. This map was established from a contig constructed with YAC, BAC, and cosmid clones and covers about 500 kb of 16p13.3. It contains nine transcriptional units corresponding to known genes or to genes belonging to known gene families, 23 gene fragments characterized by partial sequences, and an endogenous retrovirus sequence. It thus considerably increases the number of genes in this interval and improves our knowledge concerning some of the genes or gene families present in this region. Data accumulated in this region were also used in a comparative study of different methods of exon detection.

Base Sequence↗
PubMed1998

CAG/CTG and CGG/GCC repeats in human brain reference cDNAs: outcome in searching for new dynamic mutations.

CAG and CGG expansion is associated with 10 inherited neurological diseases and is thought to be involved in other human genetic diseases. To identify new candidate genes, we have undertaken a large-scale screening project for CAG/CTG ([CAG]n) and CGG/GCC ([CGG]n) repeats in human brain reference cDNAs. Here, we present the final classification for 597 cDNAs selected by CAG and CGG hybridization from two libraries (100,128 clones) and the updated characterization of [CAG]n- and [CGG]n-positive cDNAs (repeat polymorphism and cDNA localization). We have selected 124 CAG and 83 CGG hybridization-positive clones representing new genes, from which 49 CAG and 7 CGG repeats could be identified. New [CAG]n and [CGG]n with more than seven to nine units were rare (1/2000), and perfect [CAG]n 9 were more likely polymorphic. Overall, highly polymorphic to monomorphic new [CAG]n > 9 and [CGG]n > 7 were characterized. The comparison of our data with other [CAG]n and [CGG]n resources suggests that the screening of reference cDNAs leads to unique sources of new [CAG]n and [CGG]n and will enhance the study of enlarged triplet repeats in human genetic diseases.

Brain↗
PubMed1998

Identification and mapping of 26 human testis mRNAs containing CAG/CTG repeats.

Various types of pathologies, including neurodegenerative diseases, as well as different types of neoplasia, are related to genes exhibiting simple tandem repeat instabilities. In order to seek for new candidate genes for such disorders, we screened 4.10(6) human testis cDNAs for CAG- and CTG-containing clones. Among 910 positive clones, we characterized 109 cDNAs corresponding to 26 independent mRNAs. Fourteen of these mRNAs represent new genes. The corresponding clones contain between 3 and 19 consecutive CAG or CTG triplets. We assigned 15 out of these 26 genes to 14 different human chromosomes. These genes represent new potential candidates for diseases associated with CAG or CTG repeat mutations.

Chromosome Mapping↗
PubMed1998

Linkage between atopy and the IgE high-affinity receptor gene at 11q13 in atopic dermatitis families.

Atopic dermatitis is a common skin disease frequently associated with allergic disorders such as allergic rhinitis and asthma. Controversial linkage findings between atopy and markers at chromosome 11q13 led us to search chromosome 11 for genes conferring susceptibility to atopic dermatitis and atopy. Twelve families were investigated using highly polymorphic markers and a powerful model-free linkage test. Two markers gave evidence for linkage, D11S903 (P = 0.02) and FCER1B (P = 0.005). A two-point lod-score analysis between these two markers revealed significant evidence for linkage (zmax = 4.02 at (theta = 0.0). In regard to model-dependent lod-score analyses between atopic disorders and FCER1B, two-point analysis gave a lod score of z = 0.78 whereas two-locus analysis using a recessive-dominant mode of inheritance displayed a significant lod score of z = 3.55. Only 2 of 12 families showed evidence for linkage using the latter oligogenic model. In conclusion, the results of our study map the FCER1B gene in close proximity to D11S903, support the finding of Cookson et al. implicating the IgE high-affinity receptor gene (FCER1B) at 11q13, and furthermore suggest an oligogenic mode of inheritance as well as heterogeneity in the genetic susceptibility to atopy and atopic dermatitis.

Adolescent↗
PubMed1998

Genetic linkage of progressive pseudorheumatoid dysplasia to a 3-cM interval of chromosome 6q22.

Progressive pseudorheumatoid dysplasia (PPD), MIM 208230, is an autosomal-recessive disorder, clinically characterized by spondyloepiphyseal dysplasia and progressive arthropathy. Linkage analysis of three families of different geographic and ethnic origin, including 11 affected individuals, showed strong evidence for localization of a gene for progressive pseudorheumatoid dysplasia to chromosome 6q with a maximum two-point lod score for D6S1647 of 8.34 at theta=0. Analysis of regions of homozygosity placed the gene in a 3-cM interval between D6S 1594 and D6S432. No significant shared haplotype was found for markers of the linked interval in the three families analyzed. Five genes encoding collagen and one encoding a specific procollagen-processing enzyme that map near this interval represent good candidates for the PPD gene.

Arthritis, Rheumatoid↗
PubMed1998

Evidence of chromosomal inversion using fluorescence in situ hybridization to stretched DNA.

The resolution of fluorescence in situ hybridization techniques (FISH) can be improved using techniques of DNA stretching. The so-called DIRVISH technique has been used to demonstrate the existence of an inversion involving a small chromosomal segment of the long arm of chromosome 14. This inversion was suspected, but not proven, in patients with familial Alzheimer disease. Two-colour FISH using YAC and cosmid probes allowed us to limit the rearranged region around YAC 964e2, which encompasses the Presenilin 1 (PR1) gene. The existence of small-sized inversions within the genome becomes, thus, open to microscope analysis.

Age of Onset↗
PubMed1998

Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF).

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurring attacks of fever and serositis. It affects primarily North African Jews, Armenians, Turks and Arabs, in which a founder effect has been demonstrated. The marenostrin-pyrin-encoding gene has been proposed as a candidate gene for the disease ( MEFV ), on the basis of the identification of putative mutations clustered in exon 10 (M680V, M694I, M694V and V726A), each segregating with one ancestral haplotype. In a search for additional MEFV mutations in 120 apparently non-founder FMF chromosomes, we observed eight novel mutations in exon 2 (E148Q, E167D and T267I), exon 5 (F479L) and exon 10 (I692del K695R, A744S and R761H). Except for E148Q and K695R, all mutations were found in a single chromosome. Mutation E148Q was found in all ethnic groups studied and in association with a novel ancestral haplotype in non-Ashkenazi Jews (S2). Altogether, these new findings definitively establish the marenostrin/pyrin-encoding gene as the MEFV locus.

Africa, Northern↗
PubMed1998

Mapping of a complicated familial spastic paraplegia to locus SPG4 on chromosome 2p.

Autosomal dominant familial spastic paraplegia (AD-FSP) is a degenerative disorder of the central motor system characterised by progressive spasticity of the lower limbs. AD-FSP has been divided into pure and complicated forms. Pure AD-FSP is genetically heterogeneous; three loci have been mapped to chromosomes 14q (SPG3), 2p (SPG4), and 15q (SPG6), whereas no loci responsible for complicated forms have been identified to date. Here we report linkage to the SPG4 locus in a three generation family with AD-FSP complicated by dementia and epilepsy. Assuming that both forms of AD-FSP are caused by mutations involving the same FSP gene, analysis of recombination events in this family positions the SPG4 gene within a 0 cM interval flanked by loci D2S2255 and D2S2347.

Adult↗
PubMed1998

The Human Genome Project: from mapping to sequencing.

Until recently, the "human genome" programs were mainly directed towards the development of maps to identify disease genes. The genetic map comprises about 8000 highly informative second generation markers of the microsatellite type. The density of markers is now sufficient to localize a gene for a monogenic disease with a precision of 1 to 2 million base pairs easily, and to define intervals which contain susceptibility genes for multifactorial disorders. A third generation map based on single nucleotide polymorphisms that can be genotyped using DNA chip technology is in progress. The physical map, based on sets of overlapping yeast artificial chromosomes ordered using sequence-tagged sites, covers over 90% of the genome. However, this physical map cannot serve as a support for sequencing because of the numerous rearrangements that occur in yeast artificial chromosomes. An international network of laboratories has mapped a set of more than 30,000 expressed sequences from cDNAs using whole genome radiation hybrids that enable integration of genes within existing maps. The human genome program is now progressively shifting to massive sequencing, although sequence ready maps are not available for the major part of the human genome. Similarly, our capacity to interpret the available genomic sequence remains limited.

Genetic Linkage↗
PubMed1997

Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.

BACKGROUND: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is commonly overlooked or misdiagnosed owing to its recent identification and its variable mode of presentation. The defective gene in CADASIL is Notch3, which encodes a large transmembrane receptor. To set up a diagnostic test and to delineate the Notch3 domains involved in CADASIL., we undertook mutations analysis in this gene in a group of CADASIL patients. METHODS: 50 unrelated patients with CADASIL and 100 healthy controls were screened for mutations along the entire Notch3 sequence, by means of single-strand conformation polymorphism, heteroduplex, and sequence analysis. FINDINGS: Strongly stereotyped mis-sense mutations, located within the epidermal-growth-factor-like (EGF-like) repeats, in the extracellular domain of Notch3, were detected in 45 patients. Clustering of mutations within the two exons encoding the first five EGF-like repeats was observed (32 patients). All these mutations lead to loss or gain of a cysteine residue and therefore to an unpaired number of cysteine residues within a given EGF domain. None of these mutations was found in the 100 controls. INTERPRETATION: Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, and easy and reliable diagnostic test for CADASIL is feasible. The findings suggest that aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of this disorder.

Case-Control Studies↗
PubMed1997

Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.

Adult↗
PubMed1997

Association of rheumatoid arthritis with an amino acid allelic variation of the T cell receptor.

OBJECTIVE: To investigate allelic variations of T cell receptor residues for a contribution to rheumatoid arthritis (RA) susceptibility. METHODS: We conducted an RA case-control study involving 1,579 northwest Europeans: 766 patients with erosive and rheumatoid factor-positive disease and 813 control subjects. Productive changes of segments TCRAV6S1, TCRAV7S1, TCRAV8S1, TCRAV10S2, and TCRBV6S1, TCRBV6S7 were investigated by single-strand conformation polymorphisms. The TCRAV8S1 association was confirmed by restriction fragment length polymorphism. RESULTS: In the systematic study (77 patients and 119 controls), an increase in 1 TCRAV8S1 genotype was found in the RA patients (P = 0.0004). This finding was replicated in 2 further populations, one from France (212 patients and 254 controls) and the other from Britain (477 patients and 440 controls), with a similar odds ratio (OR), which allowed pooling of the data and confirmation of the association (OR 1.3 [95% confidence interval 1.1-1.7], P = 0.008). CONCLUSION: These findings show evidence that TCRA is an RA susceptibility locus.

Alleles↗
PubMed1997

Localization and expression analysis of a novel conserved brain expressed transcript, Brx/BRX, lying within the Xic/XIC candidate region.

The X inactivation center candidate region (Xic/XIC in mouse and human) is poorly characterized for the presence of transcription units. Only two conserved genes have been isolated to date, Xist/XIST and Cdx4/CDX4. The other known gene lying within this region, Tsx, has been identified so far only in rodents by analyzing the complete genomic sequence of a 94-kb region distal to Xist. Here, we report the characterization of an additional gene lying within this 94-kb sequenced region. Brx, for Brain X-linked gene, is a rare transcript preferentially expressed in the brain. It is normally X-inactivated in the mouse. Localisation of BRX, its human homolog has shown the gene to be located within the orthologous but inverted human CDX4-XIST segment. These results suggest that the gene order of the region encompassing the Cdx4-Xist interval in the mouse is similar in human. Comparison of the Xist-Brx and Brx-Cdx4 regions in mouse and human indicates that these intervals are three times longer in human than in mouse. BRX is a new potential candidate for one of the X-linked mental retardation syndromes mapped within the pericentromeric region of the human X Chromosome (Chr).

Amino Acid Sequence↗