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Biomedical subjects

J M Vance

Publications and source records attributed to J M Vance.

At least 55 records · Page 3Linked to original sources
PubMed1998

Use of a CEPH meiotic breakpoint panel to refine the locus of limb-girdle muscular dystrophy type 1A (LGMD1A) to a 2-Mb interval on 5q31.

Limb-girdle muscular dystrophy type 1A (LGMD1A) is an autosomal dominant disease characterized by progressive weakness of the hip and shoulder girdle. The gene for LGMD1A had been localized to a 7-cM interval at 5q31 in a single large family (Family 39). To refine the localization of LGMD1A further and to aid in its identification, a high-resolution physical map of the locus was used to identify and provisionally localize 25 polymorphic markers. A subset of these markers was then ordered genetically, using a CEPH meiotic breakpoint panel, resulting in an integrated physical-genetic map of the locus. Relevant markers were genotyped on the members of Family 39 who contained informative recombination events, resulting in a further narrowing of LGMD1A to an interval bounded by D5S479 and D5S594, estimated to be 2 Mb in size. Integration of the genetic and physical map permits the identification of several transcription units from within the narrowed LGMD1A interval, including one that is muscle specific, representing candidate genes for this familial dystrophy.

Chromosome Mapping↗
PubMed1998

Quantitative DNA pooling to increase the efficiency of linkage analysis in autosomal dominant disease.

DNA pooling is an efficient method to rapidly perform genome-wide linkage scans in autosomal recessive diseases in inbred populations where affected individuals are likely to be homozygous for alleles near the disease gene locus. We wanted to examine whether this approach would detect linkage in autosomal dominant (AD) disorders where affected individuals may share one allele identical by descent at loci tightly linked to the disease. Two large outbred pedigrees in which the AD diseases familial venous malformation (FVM) and hereditary hemorrhagic telangiectasia (HHT1), linked to 9p and 9q, respectively, were investigated. Separate pools of DNA from affected (n = 21 for FVM and 17 for HHT1) and unaffected family members (n = 9 FVM and HHT1), and 25 unrelated population controls were established. Polymorphic markers spanning chromosome 9 at approximately 13.5-cM intervals were amplified using standard PCR. Allele quantitation was performed with a fluorimager. Visual inspection of allele intensities and frequency distributions suggested a shift in frequency of the most common allele in the affecteds lane when compared to control lanes for markers within 30 cM of the FVM and HHT1 loci. These subjective assessments were confirmed statistically by testing for the difference between two proportions (one-sided; P < or = 0.05). When using population controls, the true-positive rates for FVM and HHT1 were 5/5 and 2/5 markers, respectively. False-positive rates for FVM and HHT1 were 3/9 and 2/9, respectively. In both AD diseases investigated, quantitative DNA pooling detected shifts in allele frequency, thus identifying areas of known linkage in most cases. The utility of this technique depends on the size of the pedigree, frequency of the disease-associated allele in the population, and the choice of appropriate controls. Although the false-positive rate appears to be high, this approach still serves to reduce the amount of overall genotyping by about 60%. DNA pooling merits further investigation as a potential strategy in increasing the efficiency of genomic linkage scans.

Alleles↗
PubMed1998

Fine localization of the CMT4A locus using a PAC contig and haplotype analysis.

Charcot-Marie-Tooth disease type 4A (CMT4A) is a severe, autosomal recessive peripheral neuropathy linked to chromosome 8q13-q21. We have previously constructed a YAC contig across the CMT4A region and narrowed the disease-flanking interval to approximately three megabases. Subsequently, we constructed a PAC/BAC contig made of 44 clones and mapped 44 new and 30 previous STSs, ESTs, and polymorphic makers to the region. Using 13 polymorphic markers, we have now identified an ancestral haplotype segregating in three families, indicating a common founder mutation. Two ancestral recombination events in this haplotype significantly reduce the minimal candidate region to a minimal trailing path of five PAC/BAC clones, which will now allow direct investigation of candidate genes for CMT4A.

Alleles↗
PubMed1998

Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy.

The Bethlem myopathy is a rare autosomal dominant proximal myopathy characterized by early childhood onset and joint contractures. Evidence for linkage and genetic heterogeneity has been established, with the majority of families linked to 21q22.3 and one large family linked to 2q37, implicating the three type VI collagen subunit genes, COL6A1 (chromosome 21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes. Mutations of the invariant glycine residues in the triple-helical domain-coding region of COL6A1 and COL6A2 have been reported previously in the chromosome 21-linked families. We report here the identification of a G-->A mutation in the N-terminal globular domain-coding region of COL6A3 in a large American pedigree (19 affected, 12 unaffected), leading to the substitution of glycine by glutamic acid in the N2 motif, which is homologous to the type A domains of the von Willebrand factor. This mutation segregated to all affected family members, to no unaffected family members, and was not identified in 338 unrelated Caucasian control chromosomes. Thus mutations in either the triple-helical domain or the globular domain of type VI collagen appear to cause Bethlem myopathy.

Amino Acid Sequence↗
PubMed1998

Coexistence of macular corneal dystrophy types I and II in a single sibship.

BACKGROUND: Macular corneal dystrophy (MCD) is an inherited autosomal recessive disorder that has been subdivided into two primary immunophenotypes, MCD types I and II. The MCD type I gene has been localised previously to chromosome 16q22 and suggestive evidence provided that MCD type II gene is also linked to this region. Here an unusual family is reported where both MCD types I and II are found in a single sibship. METHODS: Immunoreactivity to an anti-keratan sulphate monoclonal antibody (5-D-4) was evaluated in patients' serum and in corneal tissue obtained at keratoplasty. Chromosomal haplotypes were constructed using microsatellite repeat markers spanning the region of the MCD type I locus. RESULTS: Immunological studies demonstrated that two of the affected siblings have MCD type II while one has MCD type I. Haplotype analysis suggests that all three affected sibs inherited one identical parental haplotype. However, the two MCD types differ in their alternative chromosome with both MCD type II children sharing an identical haplotype, different from their MCD type I sibling. CONCLUSION: The findings in this study support the hypothesis that the genes for MCD types I and II co-localise to the same region of chromosome 16 and are likely to be due to allelic manifestations of the same abnormal gene.

Aged↗
PubMed1997

Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12.

CONTEXT: Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD. OBJECTIVE: To identify additional genetic risk factors for late-onset AD. DESIGN: A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set. SETTING: Clinic populations in the continental United States. PATIENTS: From a series of multiplex families affected with late-onset (> or =60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis. MAIN OUTCOME MEASURES: Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods. RESULTS: Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed forchromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5, 2.6, 3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOE genotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0, 2.4, 3.7, and 3.3 and a peak multipoint MLS of 3.9. CONCLUSIONS: A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20.

Age of Onset↗
PubMed1997

Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity.

The Charcot-Marie-Tooth (CMT) neuropathies are a group of disorders exhibiting neurophysical, pathological and genetic heterogeneity. CMT2 is a diagnostic subtype of this group of disorders characterized by variable expression and age-of-onset and normal or slightly diminished nerve conduction velocities. Previously, linkage and heterogeneity had been reported in CMT2 with linked families localizing to chromosome 1p (CMT2A). Recently a second CMT2 locus has been described on chromosome 7 in a single large CMT2 family (CMT2D). We have performed pedigree linkage analysis on 15 CMT2 families (N = 371 individuals, 106 affected family members) and have confirmed linkage to chromosome 7. Furthermore, using both admixture and multipoint linkage analysis we show conclusive evidence for additional heterogeneity within this clinical subtype with evidence of families that exclude linkage to both the CMT2D and CMT2A regions. In addition, unlike the previous report we found no obvious consistent clinical differences between the linked family types.

Charcot-Marie-Tooth Disease↗
PubMed1997

Locus heterogeneity, anticipation and reduction of the chromosome 2p minimal candidate region in autosomal dominant familial spastic paraplegia.

We examined 11 Caucasian pedigrees with autosomal dominant 'uncomplicated' familial spastic paraplegia (SPG) for linkage to the previously identified loci on chromosomes 2p, 14q and 15q. Chromosome 15q was excluded for all families. Five families showed evidence for linkage to chromosome 2p, one to chromosome 14q, and five families remained indeterminate. Homogeneity analysis of combined chromosome 2p and 14q data gave no evidence for a fourth as yet unidentified SPG locus. Recombination events reduced the chromosome 2p minimum candidate region (MCR) to a 3 cM interval between D2S352 and D2S367 and supported the previously reported 7 cM MCR for chromosome 14q. Age of onset (AO) was highly variable, indicating that subtypes of SPG are more appropriately defined on a genetic basis than by AO. Comparison of AO in parent-child pairs was suggestive of anticipation, with a median difference of 9.0 years (p<0.0001).

Adolescent↗
PubMed1997

Further exclusion of FSHD1B from the telomeric region of 10q.

The localization of the gene for the majority of cases of facioscapulohumeral muscular dystrophy is established as 4q35-qter (FSHD1A), although locus heterogeneity has been demonstrated with a minority of families unlinked to 4q. In FSHD1A, the disease is associated with a deletion of 3.3 kb repeats from a tandem repeat located near the as-yet-unidentified gene. This repeat cross-hybridizes with a telomeric region on 10q, making this cross-hybridizing region a feasible candidate gene for FSHD1B. We have tested the most telomeric marker on 10q (sAVA4) and excluded approximately 17 cM on either side of this marker as harboring the FSHD1B gene.

Alleles↗
PubMed1997

Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome 14q11.2-q13 in American families suggests the existence of a second causal mutation.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, autosomal dominant disorder characterized by progressive ptosis, dysphagia, and extremity weakness. Linkage of OPMD to 14q11.2-q13 has been reported in a series of French-Canadian families. Tightly linked markers have been defined and haplotype analysis in these data show a single segregating disease chromosome throughout the OPMD French-Canadian families. We have ascertained and sampled five multigenerational outbred American OPMD families. Four of the five families have known French-Canadian ancestry while the fifth is of English/Scottish origin. Linkage analysis was performed using standard likelihood methods. A peak multipoint lod score of 6.30 was obtained for the marker MYH7.1 in the OPMD families. The English/ Scottish family exhibited a different chromosomal haplotype for the OPMD alleles than the families of French-Canadian origin. These data suggest this family may represent a second, possibly independent mutation in this disorder. Linkage was confirmed to chromosome 14q11.2-q13 with no evidence of genetic heterogeneity.

Adult↗
PubMed1996

Toxicity of expanded polyglutamine-domain proteins in Escherichia coli.

Five neurodegenerative diseases are caused by proteins with expanded polyglutamine domains. Toxicity of these proteins has been previously identified only in mammals, and no simple model systems are available. In this paper, we demonstrate in E. coli that long polyglutamine domains (59-81 residues) as GST-fusion proteins inhibit growth while smaller glutamine (10-35 residues) or polyalanine (61 residues) domains have no effect. Analogously in humans, polyglutamine repeats less than 35-40 glutamines produce a normal phenotype, while expansion greater than 40 glutamines is always associated with disease. Expression of polyglutamine proteins in E. coli may help identify the molecular mechanism of pathogenesis of CAG trinucleotide repeat diseases and be a useful screen to identify potential therapeutic compound.

Amino Acid Sequence↗
PubMed1996

Periodic vestibulocerebellar ataxia, an autosomal dominant ataxia with defective smooth pursuit, is genetically distinct from other autosomal dominant ataxias.

BACKGROUND: Periodic vestibulocerebellar ataxia is an autosomal dominant disorder characterized by defective smooth pursuit, gaze-evoked nystagmus, ataxia, and vertigo. The age of onset ranges from the third to the sixth decade. To date, all patients have originated from North Carolina, suggesting a single common founder. OBJECTIVE: To clarify the classification of periodic vestibulocerebellar ataxia by determining whether it is allelic to other autosomal dominant cerebellar ataxias for which genes have been either localized or identified. METHODS: Blood was collected and DNA isolated from 66 subjects (19 affected individuals) in two multigenerational families. The microsatellite markers used in the analysis either flanked or were tightly linked to the disease gene regions. Two-point and multipoint linkage analyses were performed to define the limits of exclusion. RESULTS: Periodic vestibulocerebellar ataxia was excluded from loci linked to spinocerebellar ataxia type 1 (chromosome 6p), type 2 (chromosome 12q) type 3/Machado/Joseph disease (chromosome 14q), type 4 (chromosome 16q), and type 5 (11cent) as well as to episodic ataxia with myokymia (chromosome 12p), episodic ataxia with nystagmus (chromosome 19p), acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (chromosome 19p), and dentatorubral-pallidoluysian atrophy/Haw River syndrome (chromosome 12p). CONCLUSION: Periodic vestibulocerebellar ataxia is genetically distinct from those autosomal dominant ataxias for which chromosomal localization has been established.

Alleles↗
PubMed1996

Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome 14q11.2-q13.

Oculopharyngeal muscular dystrophy is a late-onset, autosomally dominant disorder characterized by progressive ptosis, dysphagia, and extremity weakness. Linkage of oculopharyngeal muscular dystrophy to 14q11.2-q13 has been reported in a series of French Canadian families. Haplotype analysis in these data shows a single segregating disease chromosome, suggesting a founder effect in this population. We ascertained and sampled for linkage studies 5 multigenerational American families with oculopharyngeal muscular dystrophy. Four of the 5 families have known French Canadian ancestry while the fifth is of English/Scottish origin. A peak multipoint lod score of 6.30 was obtained for the marker MYH7.1 in the families, confirming linkage to 14q11.2-q13. The English/Scottish family exhibited a different chromosomal haplotype for the oculopharyngeal muscular dystrophy alleles than did the families of French Canadian origin. These data suggest that this family may represent a second, possibly independent mutation in this disorder.

Age of Onset↗
PubMed1996

Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.

At least five adult-onset neurodegenerative diseases, including Huntingtin disease (HD), and dentatorubral-pallidoluysian atrophy (DRPLA) are produced by genes containing a variably increased CAG repeat within the coding region. The size range of the repeats is similar in all diseases; unaffected individuals have fewer than 30 CAG repeats, whereas affected patients usually have more than 40 repeats. The size of the inherited CAG repeat correlates with the severity and age of disease onset. The CAG triplet repeat produces a polyglutamine domain in the expressed proteins. All of these diseases are inherited in a dominant fashion, and a pathologic gain of function in gene carriers has been proposed. We sought to identify proteins in the brain that selectively interact with polyglutamine-domain proteins, hypothesizing that the polyglutamine domain may determine protein-protein interactions.

Adult↗
PubMed1996

Evidence for locus heterogeneity in the Bethlem myopathy and linkage to 2q37.

The Bethlem myopathy, a childhood onset autosomal dominant myopathy with joint contractures, has recently been localized to 21q in a series of Dutch families and the alpha 1 and alpha 2 subunits of type VI collagen (COL6A1 and COL6A2) have been postulated as candidate genes. We investigate a large family of French Canadian descent (family 1489) in which the Bethlem myopathy is segregating. Family 1489 is unlinked to the region of interest on 21q, thus demonstrating locus heterogeneity within the Bethlem myopathy classification. In view of the localization of the genes coding the alpha 1 and alpha 2 subunits of type VI collagen on chromosome 21q, we carried out linkage analysis on chromosome 2q where the alpha 3 subunit of type VI collagen has been localized. We demonstrate linkage to markers in this region, define the region of disease gene localization, and confirm by FISH analysis that COL6A3 is located within the interval of interest making COL6A3 a feasible candidate gene for the Bethlem myopathy.

Chromosome Mapping↗