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J Wasmuth

Publications and source records attributed to J Wasmuth.

At least 19 recordsLinked to original sources
PubMed1996

Identification and characterization of two novel tetratricopeptide repeat-containing genes.

The tetratricopeptide repeat (TPR) is a degenerate, repeating amino acid motif of 34 residues that has been identified in a variety of proteins; however, no biochemical function has been established for it. In a two-hybrid screen for interaction with the GAP-related domain of neurofibromin, the product of the NF1 gene, we have identified two novel human genes encoding proteins with TPR motifs. The first, represented by cDNA tpr1, is located in chromosome 5q32-33.2. It is ubiquitously expressed as a 1.6-kb transcript that encodes three tandem TPR motifs, but is not related to any other known gene outside this domain. The second, defined by cDNA tpr2, maps to human chromosome 17q11.2-23. It is ubiquitously expressed as a 2.2-kb transcript encoding seven TPR units. Interestingly, a separate region of the tpr2 cDNA has striking similarity to the "J region" of the DnaJ family. The products of the tpr1 and tpr2 cDNAs interact preferentially with a truncated form of the NF1 GAP-related domain via their TPR regions, suggesting that they may be targeted to an abnormality of protein folding.

Amino Acid Sequence↗
PubMed1996

Clinical evidence of genetic anticipation in adult-onset idiopathic dystonia.

Idiopathic dystonia occurs in both hereditary and sporadic forms. In this report, we studied the age of onset and family history of 260 patients (probands) with idiopathic adult-onset dystonia (IAD), cranial or cervical. The mean age at onset of these patients was (45.71 +/- 15.85) years. Forty-nine probands had a positive family history of dystonia or tremor in first- and second-degree relatives, and 7 had affected siblings only. The significance of tremor as a part of clinical manifestation of dystonia was evidenced by a high frequency of postural or action tremor in patients and relatives. Retrospectively, we examined the age of onset of dystonia (cervical or cranial) on successive generations in 49 families. Age of onset of clinical symptoms was earlier, by an average of 21.25 years, in the second generation than in the first generation. The mean age at onset of affected family members differed significantly between successive generations in these 49 families (p = 1.11 x 10(-8)). Our results suggest a tendency for earlier onset of dystonia and worsening of disease phenotype in succeeding generations in the same family. These findings are most compatible with genetic anticipation and suggest that an unstable trinucleotide repeat is most likely involved in adult-onset primary cranial or cervical dystonia. In addition, tremor as an integral part of dystonia needs further evaluation by molecular genetic studies.

Adult↗
PubMed1993

A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13.

We have constructed a contig of non-chimaeric yeast artificial chromosomes (YACs) across the candidate region for childhood autosomal recessive spinal muscular atrophy (SMA) in 5q13. A novel microsatellite reduces the candidate region to approximately 400kb of DNA distal to D5S435. The candidate region contains blocks of chromosome 5 specific repeats which have copies on 5p as well as elsewhere on 5q. Restriction mapping of the YACs reveals at least one CpG island in the SMA gene region. The YAC maps indicate that the contig contains minimal rearrangements or deletions. The data show the value of screening several YAC libraries simultaneously in order to construct a set of overlapping sequences suitable for candidate gene searches and direct genomic sequencing.

Base Sequence↗
PubMed1992

FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter.

The receptors for at least two hematopoietic growth factors, namely the stem cell factor and colony-stimulating factor 1, belong to class III receptor tyrosine kinases. Here we describe cloning of a partial complementary DNA for FLT4, an additional member of this gene family from human leukemia cells. The FLT4 tyrosine kinase domain is 79% homologous with the previously cloned FLT1 (M. Shibuya et al., Oncogene, 5: 519-524, 1990) tyrosine kinase and maps to the chromosomal region 5q33-qter. We have found FLT4 expression in human placenta, lung, heart, and kidney, whereas the pancreas and brain appeared to contain very little if any FLT4 RNA. The results suggest that FLT4 functions in multiple adult tissues.

Adult↗
PubMed1992

Assay by polymerase chain reaction (PCR) of multi-allele polymorphisms in the Huntington's disease region of chromosome 4.

The Huntington's disease-linked D4S115 marker has been converted from a DNA blot assay to a more sensitive and rapid polymerase chain reaction (PCR) assay. PCR amplification of a tandem repeat at D4S115 revealed 7 allelic fragments, ranging in size from approximately 610 to 915 bp, differing in their apparent copy number of a approximately 55 bp core repeat. This repeat unit differs strikingly in sequence from the repeat units of other multi-allele markers from chromosome region 4p 16.3, arguing that the VNTR (Variable Number of Tandem Repeats) loci clustered in this region did not arise from a common ancestral sequence. The D4S115 marker can be assayed simultaneously with PCR products from D4S125, D4S95 and D4S43 on a single agarose gel, providing a rapid scan for successful amplification of these difficult-to-assay VNTRs, and for inheritance of the entire candidate Huntington's disease region. This approach should help to increase the speed, informativeness and accuracy of presymptomatic and prenatal linkage testing in this devastating disorder.

Alleles↗
PubMed1991

A genetic linkage map of human chromosome 5 with 60 RFLP loci.

A genetic map of human chromosome 5 that contains 60 restriction fragment length polymorphism (RFLP) loci in one linkage group has been constructed. Segregation data using these markers and 40 large multigenerational families supplied by the Centre d'Etude du Polymorphisme Humain have been collected. Linkage analyses were performed with the program package CRI-MAP; using odds greater than 1000:1, 30 RFLP loci could be placed on the map. This genetic map spans 289 cM sex-equal, 353 cM in females, and 244 cM in males. While the relative rate of recombination for female meioses is nearly twice that of males over much of the chromosome, several instances of statistically significant excess male recombination were observed. The order of probes on the genetic map has been confirmed by their physical order as determined by somatic cell hybrid lines containing deletions of normal chromosome 5. There is concordance between the physical positions of markers and their genetic positions. Our most distal probes on the genetic map are cytologically localized to the most distal portions of the chromosome. This suggests that our genetic map spans most of chromosome 5.

Blotting, Southern↗
PubMed1991

Complex patterns of linkage disequilibrium in the Huntington disease region.

The genetic defect causing Huntington disease (HD) has been mapped to 4p16.3 by linkage analysis using DNA markers. Two apparently contradictory classes of recombination events in HD kindreds preclude precise targeting of efforts to clone the disease gene. Here, we report a new recombination event that increases support for an internal candidate region of 2.5 Mb between D4S10 and D4S168. Analysis of 23 DNA polymorphisms in 4p16.3 revealed a complex pattern of association with the disease gene that failed to narrow the size of the candidate region. The degree of linkage disequilibrium did not show a continuous increase across the physical map, nor was a region of extreme disequilibrium identified. Markers displaying no association with the disorder were interspersed with and, in many cases, close to markers displaying significant disequilibrium. Comparison of closely spaced marker pairs on normal and HD chromosomes, as well as analysis of haplotypes across the HD region, suggest that simple recombination subsequent to a single original HD mutation cannot easily explain the pool of HD chromosomes seen today. A number of different mechanisms could contribute to the diversity of haplotypes observed on HD chromosomes, but it is likely that there has been more than one and possibly several independent origins of the HD mutation.

Alleles↗
PubMed1989

Evidence from family studies that the gene causing Huntington disease is telomeric to D4S95 and D4S90.

A DNA probe (D4S95) that detects a variable number of tandem repeats and a single-site-variation polymorphism after digestion with a single restriction enzyme, AccI, has previously been described. The order of this probe relative to the gene for Huntington disease (HD) and other previously described markers has not been established. Analysis of 24 affected families with HD has shown that D4S95 is in tight linkage with the gene causing HD, with a maximal Lod score of 12.489 at a theta of .03. D4S90 is a probe which maps to 4p16.3, telomeric to D4S95, and detects polymorphisms with HincII and other enzymes. In one affected person, recombination has occurred between D4S10 and HD, between D4S95 and HD, and in all likelihood also between D4S90 and HD, which strongly suggests that the gene for HD is telomeric to all these DNA probes. This suggests that the gene causing HD is located in the most distal region of the short arm of chromosome 4, flanked by D4S90 and the telomere, and supports the locus order D4S10-D4S95-D4S90-HD-telomere. D4S95 is a most useful DNA marker for predictive testing programs, while D4S90 will serve as a useful starting point for identifying DNA fragments closer to the gene for HD.

Female↗
PubMed1988

Localization of a susceptibility locus for schizophrenia on chromosome 5.

Schizophrenia is a common disorder with a life time prevalence of approximately 1 per cent. The illness often develops in young adults, who were previously normal, and is characterized by a constellation of symptoms including hallucinations and delusions (psychotic symptoms) and symptoms such as severely inappropriate emotional responses, a disorder of thinking and concentration, erratic behaviour as well as social and occupational deterioration. A considerable proportion of the variance in the liability to develop schizophrenia may be genetic, but segregation analysis, to establish a mode of transmission, has not produced a consistent result. One of these studies was carried out in Iceland and made use of the large family size and extensive geneaological information present in that country. Here we demonstrate genetic linkage of two DNA polymorphisms on the long arm of human chromosome 5 to schizophrenia in seven British and Icelandic families with multiple affected members. The results indicate the existence of a gene locus with a dominant schizophrenia-susceptibility allele. Inheritance of the allele in the families studied suggests that it may also predispose to psychiatric conditions such as schizophrenia spectrum disorders and a variety of other disorders. This report provides the first strong evidence for the involvement of a single gene in the causation of schizophrenia.

Chromosomes, Human, Pair 5↗
PubMed1988

Localization of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5.

Familial adenomatous polyposis (FAP), a Mendelian disorder that includes familial polyposis coli (FPC) and Gardner syndrome (GS), has an autosomal dominant mode of inheritance. It is characterized by hundreds to thousands of adenomatous polyps that can progress to carcinoma of the colon, suggesting that the gene that harbors the FAP germ-line mutation may play an important role in the somatic genetic pathway to colon cancer. The defect responsible for FAP was recently mapped to the long arm of chromosome 5 by linkage between the FPC phenotype and a locus defined by DNA probe pC11p11 (D5S71), located at 5q21-22. Because an important next step in the paradigm for identification of a disease gene is to obtain a more precise localization, we isolated and mapped by linkage six additional polymorphic DNA markers in the FAP region. Subsequent linkage analysis in six pedigrees, three having the FPC phenotype and three segregating GS, placed the FAP locus very close to a new marker, YN5.48 (D5S81), that is approximately 17 centimorgans distal to C11p11 on the genetic map. The analysis revealed no evidence of genetic heterogeneity between the two phenotypes, a question that had not been clearly resolved by the earlier studies. The new set of markers in the near vicinity of the FAP locus represents a further step toward isolation of the genetic defect and provides the opportunity for preclinical diagnosis of risk status for colon cancer among individuals in families that are segregating adenomatous polyposis.

Adenomatous Polyposis Coli↗
PubMed1988

Improved predictive testing for Huntington disease by using three linked DNA markers.

Eighty-five persons at risk for Huntington disease (HD) have enrolled in a predictive-testing pilot program. Informativeness of the test has been determined for 41 of these candidates by using linked DNA probes. Nine (21.9%) of these persons have been excluded from the test as a result of the unavailability of DNA from crucial family relatives. Homozygosity for all of the three DNA markers (D4S10, D4S62, and D4S95) was not found in any affected parent. Only one (2%) of the 41 test candidates has had an uninformative result. Results have been given to 20 persons, of whom 12 (60%) received a decreased risk and eight (40%) received an increased risk of having inherited the mutant gene for HD. The combined use of three DNA markers significantly increases the informativeness of family structures such that some change in the estimation of genetic risk is now possible for approximately 75% of all persons who request predictive testing.

Adult↗
PubMed1986

Assignment of human 3-hydroxy-3-methylglutaryl coenzyme A reductase gene to q13----q23 region of chromosome 5.

We have used hamster cDNA probes for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (HMGCR) to determine the chromosomal location of the human gene for HMG CoA reductase. Southern blot analysis of genomic DNA from 16 independent mouse-human somatic cell hybrids showed that the human gene for HMG CoA reductase resides on chromosome 5. Analysis of Chinese hamster-human somatic cell hybrids selectively retaining human 5 or a portion of it showed that the gene locus for HMG CoA reductase can be assigned to the q13----q23 region of chromosome 5.

Animals↗