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J Weissenbach

Publications and source records attributed to J Weissenbach.

At least 217 records · Page 12Linked to original sources
PubMed1995

Autosomal dominant familial spastic paraplegia: reduction of the FSP1 candidate region on chromosome 14q to 7 cM and locus heterogeneity.

Three large pedigrees of German descent with autosomal dominant "pure" familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigrees D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP.

Alleles↗
PubMed1995

The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2.

SCA3, the gene for spinal cerebellar ataxia 3, was recently mapped to a 15-cM interval between D14S67 and D14S81 on chromosome 14q, by linkage analysis in two families of French ancestry. The SCA3 candidate region has now been refined by linkage analysis with four new microsatellite markers (D14S256, D14S291, D14S280, and AFM343vf1) in the same two families, in which 19 additional individuals were genotyped, and in a third French family. Combined two-point linkage analyses show that the new markers, D14S280 and AFM343vf1, are tightly linked to the SCA3 locus, with maximal lod scores, at recombination fraction, (theta) = .00, of 7.05 and 13.70, respectively. Combined multipoint and recombinant haplotype analyses localize the SCA3 locus to a 3-cM interval flanked by D14S291 and D14S81. The same allele for D14S280 segregates with the disease locus in the three kindreds. This allele is frequent in the French population, however, and linkage disequilibrium is not clearly established. The SCA3 locus remains within the 29-cM region on 14q24.3-q32.2 containing the gene for the Machado-Joseph disease, which is clinically related to the phenotype determined by SCA3, but it cannot yet be concluded that both diseases result from alterations of the same gene.

Adult↗
PubMed1995

Refining the localization of the PKD2 locus on chromosome 4q by linkage analysis in Spanish families with autosomal dominant polycystic kidney disease type 2.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder. At least two distinct forms of ADPKD are now well defined. In approximately 86% of affected European families, a gene defect localized to 16p13.3 was responsible for ADPKD, while a second locus has been recently localized to 4q13-q23 as candidate for the disease in the remaining families. We present confirmation of linkage to microsatellite markers on chromosome 4q in eight Spanish families with ADPKD, in which the disease was not linked to 16p13.3. By linkage analysis with marker D4S423, a maximum lod score of 9.03 at a recombination fraction of .00 was obtained. Multipoint linkage analysis, as well as a study of recombinant haplotypes, placed the PKD2 locus between D4S1542 and D4S1563, thereby defining a genetic interval of approximately 1 cM. The refined map will serve as a genetic framework for additional genetic and physical mapping of the region and will improve the accuracy of presymptomatic diagnosis of PKD2.

Adult↗
PubMed1995

Microsatellite-based fine mapping of the Van der Woude syndrome locus to an interval of 4.1 cM between D1S245 and D1S414.

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder characterized by lip pits, clefting of the primary or secondary palate, and hypodontia. The gene has been localized, by RFLP-based linkage studies, to region 1q32-41 between D1S65-REN and D1S65-TGFB2. In this study we report the linkage analysis of 15 VWS families, using 18 microsatellite markers. Multipoint linkage analysis places the gene, with significant odds of 2,344:1, in a 4.1-cM interval flanked by D1S245 and D1S414. Two-point linkage analysis demonstrates close linkage of VWS with D1S205 (lod score [Z] = 24.41 at theta = .00) and with D1S491 (Z = 21.23 at theta = .00). The results revise the previous assignment of the VWS locus and show in an integrated map of the region 1q32-42 that the VWS gene resides more distally than previously suggested. When information about heterozygosity of the closely linked marker D1S491 in the affected members of the VWS family with a microdeletion is taken into account, the VWS critical region can be further narrowed, to the 3.6-cM interval between D1S491 and D1S414.

Abnormalities, Multiple↗
PubMed1995

A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13.

Fundus flavimaculatus with macular dystrophy is an autosomal recessive disease responsible for a progressive loss of visual acuity in adulthood, with pigmentary changes of the macula, perimacular flecks, and atrophy of the retinal pigmentary epithelium. Since this condition shares several clinical features with Stargardt disease, which has been mapped to chromosome 1p21-p13, we tested the disease for linkage to chromosome 1p. We report here the mapping of the disease locus to chromosome 1p13-p21, in the genetic interval defined by loci D1S435 and D1S415, in four multiplex families (maximum lod score 4.79 at recombination fraction 0 for probe AFM217zb2 at locus D1S435). Thus, despite differences in the age at onset, clinical course, and severity, fundus flavimaculatus with macular dystrophy and Stargardt disease are probably allelic disorders. This result supports the view that allelic mutations produce a continuum of macular dystrophies, with onset in early childhood to late adulthood.

Alleles↗
PubMed1994

Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene.

Induction of testis development in mammals requires the presence of the Y-chromosome gene SRY. This gene must exert its effect by interacting with other genes in the sex-determination pathway. Cloning of a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both bone formation and control of testis development.

Amino Acid Sequence↗
PubMed1994

Yeast artificial chromosome and radiation hybrid map of loci in chromosome band 8p22, a common region of allelic loss in multiple human cancers.

Polymorphic alleles at loci such as LPL (lipoprotein lipase) and MSR (macrophage scavenger receptor) in chromosome band 8p22 are frequently lost during the genesis of several types of human cancer, including colorectal, non-small cell lung, hepatocellular, and prostatic carcinomas. A physical map of 31 published or novel probes and sequence-tagged sites in this genetic region was constructed using a radiation hybrid panel and the CEPH (Centre d'Etude du Polymorphisme Humain) yeast artificial chromosome (YAC) library. Thirty-six overlapping YACs defined a physical order for the following polymorphic markers: tel-D8S26-D8S511-D8S549-MSR-D8S254-D8S233- D8S261-D8S21-LPL-D8S258-cen. These maps unify small consensus regions of allelic loss on chromosome 8p defined by restriction fragment length polymorphisms with more informative PCR-based polymorphisms and widely available YAC mapping resources.

Alleles↗
PubMed1994

Linkage analyses in British pedigrees suggest a single locus for Darier disease and narrow the location to the interval between D12S105 and D12S129.

Darier disease is a dominantly inherited skin disorder in which there appears to be abnormal adhesion between keratinocytes. We and others have shown that the disease in some British pedigrees is closely linked to markers mapping to 12q23-q24.1. In the present study we have defined crossovers that enable us to narrow the location of the disease gene to the interval between the D12S105 and the D12S129 markers. This interval may be expected to be on the order of about 4 cM on the basis of linkage data obtained using the primary CEPH reference families. Our data provide further evidence for locus homogeneity: each of four large British pedigrees, two of which have previously been subjected to preliminary characterization, shows statistically significant evidence for linkage to markers mapping to 12q23-q24.1.

Chromosome Mapping↗
PubMed1994

Analysis of 133 meioses places the genes for nevoid basal cell carcinoma (Gorlin) syndrome and Fanconi anemia group C in a 2.6-cM interval and contributes to the fine map of 9q22.3.

Four disease genes (NBCCS, ESS1, XPAC, FACC) map to 9q22.3-q31. A fine map of this region was produced by linkage and haplotype analysis using 12 DNA markers. The gene for nevoid basal cell carcinoma syndrome (NBCCS, Gorlin) has an important role in congenital malformations and carcinogenesis. Phase-known recombinants in a study of 133 meioses place NBCCS between (D9S12/D9S151) and D9S176. Haplotype analysis in a two-generation family suggests that NBCCS lies in a smaller interval of 2.6 cM centromeric to D9S287. These flanking markers will be useful clinically for gene tracking. Recombinants also map FACC (Fanconi anemia, group C) to the same region, between (D9S196/D9S197) and D9S287. The recombination rate between (D9S12/D9S151) and D9S53 in males is 8.3% and 13.2% in females, giving a sex-specific male:female ratio of 1:1.6 and a sex-averaged map distance of 10.4 cM. No double recombinants were detected, in agreement with the apparently complete level of interference predicted from the male chiasmata map.

Basal Cell Nevus Syndrome↗
PubMed1994

The gene for a recessively inherited human childhood progressive epilepsy with mental retardation maps to the distal short arm of chromosome 8.

A recently delineated childhood epilepsy has hitherto been observed only in a small geographic region in northern Finland, where, with the exception of one, both parents of all of the 11 sibships with affected individuals descend from one or two founding couples. The disease is characterized by generalized tonic-clonic seizures with onset at 5-10 years and progressive, severe mental retardation with onset 2-5 years after the first seizures. In this study the gene locus is assigned to the telomeric region of chromosome 8p by linkage. Analyses of recombinations place the locus in the 7-centimorgan interval between AFM185xb2 and D8S262 in which three markers, D8S504, D8S264, and AFM077yg5, show no recombinations with the phenotype. Haplotypes comprising alleles at the above five loci support the hypothesis of a single founding mutation for all affected chromosomes except the one belonging to the unrelated parent, who has a very different haplotype, suggesting another mutation or a very old ancestry of a single mutation. This study raises to three the number of heritable epilepsies whose gene loci have been mapped and provides a starting point for the cloning of the gene. It also suggests the possibility that the disease might not be limited to the northern Finnish population.

Adult↗
PubMed1994

Non-specific X-linked mental retardation: linkage analysis in MRX2 and MRX4 families revisited.

We have previously reported linkage analysis in 3 families with non-specific X-linked mental retardation (XLMR). This used RFLPs and was limited by the relatively low informativeness and density of markers available. We have performed a new linkage analysis using microsatellites (including new Genethon markers) in the two most informative families. In the MRX2 family, a lod score of 2.61 at theta = 0.05 had previously been obtained with DXS85 in Xp22.2. We now report a tighter linkage with AFM 135xe7 (DXS989, z = 4.62 at theta = 0.00) and established the order DXS85-DXS207-DXS999 (AFM234 y12)-MRX2, DXS365, DXS1052 (AFM 163yh2), DXS989-DXS1065 (AFM224zf2), DMD 3'. The localization of MRX2 in Xp22.2-p22.1 is thus clearly different from the more distal MRX gene defined by patients with contiguous gene syndromes. In the MRX4 family, a maximum lod score of 2.53 at theta = 0.00 had been obtained with DXS159 in Xq13. Our present study did not show recombination from ALAS2 in Xp11.21 to DXS441 in Xq13.3 (z = 3.38 at theta = 0.00 for the latter marker) and the closest flanking markers are DXS255 in Xp11.22 and DXYS1 in Xq21.3. Reduced recombination around the centromere prevents precise mapping. The localisation of MRX4 overlaps with that of several other MRX families.

Chromosome Mapping↗
PubMed1994

Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive progressive tubulo-interstitial kidney disorder, responsible for 6-10% of end-stage renal failure in children, and is frequently associated with Leber amaurosis (termed Senior-Løken syndrome). The biochemical basis of NPH is unknown. We recently reported linkage of the purely renal form of NPH to three markers on chromosome 2. Our results also suggested the existence of genetic heterogeneity between NPH and SLS. To map this NPH gene more precisely, we have now tested the segregation of six new microsatellite markers and five additional families. Haplotype analyses show unequivocally that four NPH families are not linked to the chromosome 2 markers, although there are no clinical or pathological features discernible in these families that could separate them from the families linked to the chromosome 2 NPH locus (NPH1). This reveals genetic heterogeneity in the purely renal form of NPH. In situ hybridization of YAC clones isolated with two closely linked markers assigned the NPH1 region to 2q13. Furthermore, based on haplotype analysis and specific recombination events, the NPH1 gene has been placed between D2S293/D2S340 and D2S121, a genetic interval of about 5-7 cM.

Chromosomes, Human, Pair 2↗
PubMed1994

A YAC contig in 6p23 based on sequence tagged sites.

A yeast artificial chromosome (YAC) contig located in 6p23 and spanning roughly 2.5 Mb has been constructed from the content of 10 sequence tagged sites (STSs) for YAC clones in 66 yeast colonies. Nine of the STSs have been genetically mapped in CEPH families. The order of STSs mapped with the contig is consistent with that of the genetic map. The order of loci that did not recombine with each other on the genetic map was inferred from the contig. Various regions of the contig are covered by multiple YAC clones that complement observed STS deletions. The STS for the CAG repeat sequence contained in the gene for spinal cerebellar ataxia 1 (gene symbol SCA1) is localized in the contig. It is likely that this gene is located in 6p23. The frequency of chimeric YAC clones in this contig is 35%. Eleven yeast colonies were found to carry two or more YACs. YAC subclones from some of these colonies showed size variation, and for several subclones, evidence consistent with deletion of a sequence tagged site.

Base Sequence↗
PubMed1994

Physical localization of microsatellite markers at the ataxia-telangiectasia locus at 11q22-q23.

The autosomal recessive disorder ataxia-telangiectasia (A-T) is genetically heterogeneous, with four complementation groups. The genes for the two major groups (ATA and ATC) have been mapped to 11q22-q23. Genetic analysis of the disease has been conducted to date using biallelic polymorphisms. We have physically mapped to this region eight new microsatellite markers that were generated by three laboratories that construct whole-genome linkage maps. These markers should be valuable for refined localization and positional cloning of the A-T genes and for diagnostic purposes. The results demonstrate the value of integrating genetic and physical maps generated by different laboratories.

Ataxia Telangiectasia↗
PubMed1994

Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families.

A susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC) was recently shown to be due to mutations in the MSH2 gene on chromosome 2p. A second susceptibility locus has been mapped to chromosome 3p in two families. The present report describes the results of a genetic study of Finnish HNPCC kindreds. Of 18 apparently unrelated families living in different parts of the country, 11 could be genealogically traced to a common ancestry dating at least 13 generations back in a small geographic area. Linkage studies were possible in 9 families, revealing conclusive or probable linkage to markers on 3p in 8. Five of these were among those having shared ancestry. The location of the gene was refined by a linkage study comprising 12 marker loci. By analysis of recombinations in such families, the HNPCC locus could be assigned to the 1-centimorgan interval between marker loci D3S1561 and D3S1298. A haplotype encompassing 10 centimorgans around the HNPCC locus was conserved in five of the pedigrees with shared ancestry and present in 2 further families in which linkage analysis was not possible. Our results suggest the presence of a widespread single ancestral founding mutation. Moreover, the map position of the 3p gene for HNPCC susceptibility was greatly refined.

Adenoma↗
PubMed1994

A 1.8-Mb YAC contig in Xp11.23: identification of CpG islands and physical mapping of CA repeats in a region of high gene density.

The genes ARAF1, SYN1, TIMP, and PFC are clustered within 70 kb of one another, and, as reported in the accompanying paper (J. Knight et al., 1994, Genomics 21: 180-187), at least four more genes map within 400 kb: a cluster of Krüppel-type zinc finger genes (including ZNF21, ZNF41, and ZNF81) and ELK-1, a member of the ets oncogene superfamily. This gene-rich region is of particular interest because of the large number of disease genes mapping to Xp11.23: at least three eye diseases (retinitis pigmentosa type 2, congenital stationary night blindness CSNB1, and Aland Island eye disease), Wiskott-Aldrich syndrome, X-linked nephrolithiasis, and a translocation breakpoint associated with synovial sarcoma. We have constructed a 1.8-Mb YAC contig in this region, confirming the link between TIMP and OATL1 reported by Knight et al. (1994) and extending the map in the distal direction. To investigate the likelihood that more genes are located within this region, we have carried out detailed mapping of rare-cutter restriction sites in these YACs and identified seven CpG islands. At least six of these islands are located over 50 kb from any known gene locations, suggesting that the region contains at least this many as yet unidentified genes. We have also mapped the physical locations of six highly polymorphic CA repeats within the contig, thus integrating the physical, genetic, and transcriptional maps of the region and facilitating the mapping and identification of disease genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Genetic heterogeneity of Usher syndrome type 1 in French families.

Usher syndrome type 1 (US1) is an autosomal recessive disease characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa, and constant vestibular dysfunction. Three localizations have been described in US1: USH1A, 14q32; USH1B, 11q13.5; and USH1C, 11p15. Studying a series of 33 affected individuals belonging to 20 US1 pedigrees of French ancestry, we found that none of the three localizations accounted for all US1 families in our series (Zmax = 1.48 at theta = 0.10; Zmax = 1.45 at theta = 0.10; and Zmax = 0.36 at theta = 0.20 for probes MLJ14, Zd5, and Mfd58, respectively, at loci D14S13, D11S527, and D11S419, respectively). However, when our sample was split into two groups according to the geographic origin of the probands' grandparents, we were able to confirm the presence of a gene for US1 on chromosome 14q32 (USH1A) in 9 families originating from the Poitou region in Western France (Department of Deux-Sèvres; Zmax = 4.46 at theta = 0 for probe MLJ14 at the D14S13 locus, Morton likelihood ratio test, P < 0.01). Moreover, we refined the genetic mapping of USH1A by showing that the disease gene maps to the D14S13 locus, within the genetic interval defined by loci D14S78 and D14S250 (location score in log base 10 = 4.90). Consistent with this, nonsignificant lod score values for linkage to either USH1B or USH1C were found in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosomes, Human, Pair 11↗