Article

Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromsome 4q35 recombination events.

Collaborative Research, Inc. Waltham, Massachusetts 02154.
Nature Genetics (Impact Factor: 29.65). 07/1993; 4(2):165-9. DOI: 10.1038/ng0693-165
Source: PubMed

ABSTRACT A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been linked to polymorphisms on chromosome 4q35. Multipoint linkage analyses have placed this gene distal to all reported genetic markers on the chromosome. By using as a probe a clone isolated from a cosmid containing sequences related to a homeobox domain, de novo DNA rearrangements were reported in sporadic and familial cases of FSHD. Linkage analysis of an EcoRI polymorphism detected by this clone in twenty-four multigenerational FSHD families revealed recombinants between this marker and the disease with a recombination fraction of 0.05. Two families with apparent germline mosaicism were also identified.

0 Bookmarks
 · 
64 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) has been found to be linked to chromosome 4qter. A chromosome 4q35-ter marker, pFR-1 (subclone of the cosmid c51), has been recently isolated and used as a probe for mapping near, or within, the FSHD gene. To examine FSHD-associated DNA rearrangements in the Taiwan population, we used the pFR-1 probe to perform Southern blot analysis on 142 individuals, including 32 FSHD patients within 9 autosomal dominant families, five sporadic FSHD patients from 4 families (include one pair of twins), three sporadic scapuloperoneal syndrome (SPS) patients and two sporadic polymyositis patients with their unaffected parents, and 29 healthy controls. In 29 healthy individuals, 3 SPS and 2 polymyositis patients with their families, probe pFR-1 analysis revealed that all had polymorphic restriction fragments that were larger than 28 kb in length. All but 1 FSHD-affected individual had specific smaller EcoRI fragments (ranging in size from 10.5 to 27 kb). Two point linkage analysis between pFR-1 and the FSHD locus provided significant evidence for FSHD linkage (Zmax=6.84). A similar smaller fragment was also present in 5 sporadic patients, while this smaller fragment could not be found in one of their parents. Identical EcoRI restriction fragment length polymorphism (RFLP) patterns linked to FSHD were shown in the monozygotic twins, even though they showed extreme variability in the expression of FSHD. We conclude that the pFR-1 probe is a tightly linked marker of FSHD and can be used to detect most DNA rearrangements associated with this disease in the Taiwan population. However, the same RFLP patterns may represent extreme variability in the expression of the FSHD gene.
    Journal of the Neurological Sciences 07/1997; 149(1):73-79. · 2.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. It is an autosomal-dominant myopathy caused by a reduction in the copy number of the D4Z4 macrosatellite repeat located at chromosome 4q35. Interestingly, the reduction of D4Z4 copy number is not sufficient by itself to cause FSHD. A number of epigenetic events appear to affect the severity of the disease, its rate of progression, and the distribution of muscle weakness. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, are altered at the disease locus, causing the de-regulation of 4q35 gene expression and ultimately FSHD.
    The Journal of Cell Biology 12/2010; 191(6):1049-1060. · 9.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited disorder with an initially restricted pattern of weakness. Early involvement of the facial and scapular stabilizer muscles results in a distinctive clinical presentation. Progression is descending, with subsequent involvement of either the distal anterior leg or hip-girdle muscles. There is wide variability in age at onset, disease severity, and side-to-side symmetry, which is evident even within affected members of the same family. Although FSHD is considered a relatively benign dystrophy by some, as many as 20% of patients eventually become wheelchair-bound. Associated nonskeletal muscle manifestations include high-frequency hearing loss as well as retinal telangiectasias, both of which are rarely symptomatic. The causal genetic lesion in FSHD was described over a decade ago, raising hope that knowledge about its molecular and cellular pathophysiology was soon to follow. In the vast majority of cases, FSHD results from a heterozygous partial deletion of a critical number of repetitive elements (D4Z4) on chromosome 4q35; yet, to date, no causal gene has been identified. The accumulating evidence points to a complex, perhaps unique, molecular genetic mechanism. The absence of detectable expressed sequences from D4Z4, the association of FSHD-causing 4q35 deletions with a specific distal genomic sequence (4qA allele), altered DNA methylation patterns on 4q35, as well as other direct and indirect evidence point to epigenetic mechanisms. As a consequence, partial deletion of D4Z4 results in a (local) chromatin change and ultimately results in the loss of appropriate control of gene expression. There is at present no effective treatment for FSHD. A better understanding of the underlying pathophysiology is needed to design targeted interventions. Despite these limitations, however, two randomized controlled clinical trials have been conducted on FSHD. These trials, along with a previous natural history study, have helped to better define outcome measures for future trials in FSHD as well as other dystrophies. Muscle Nerve, 2006
    Muscle & Nerve 06/2006; 34(1):1 - 15. · 2.31 Impact Factor