Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease that has been linked to deletions within a tandem array of 3.2 kb repeats adjacent to the telomere of 4q. These repeats are also present in other locations in the human genome, including the short arms of all the acrocentric chromosomes. Here, we examine two models for the role of this repeat in FSHD. First, because of the extensive similarity between the 3.2 kb repeats on 4q and those adjacent to rDNA on the acrocentric chromosomes, we investigated whether the FSHD region on 4q is involved in sub-nuclear localization, specifically to the nucleolus. The results likely exclude any involvement of nucleolar localization in the development of FSHD. Second, we investigated a model that suggests that a functional gene may be buried within the tandem array of 3.2 kb repeats. Toward this end, we evaluated the evolutionary conservation of the repeat and a double homeodomain sequence within the repeat in a variety of primate species. The genomic organization of the 3.2 kb repeat in humans, great apes and lower primates identified the FSHD-associated repeat on chromosome 4q as the likely ancestral copy. The sequence of the rhesus monkey double homeodomain reveals significant sequence identity with the human 4q sequence. These results strongly suggest a functional role for a component of the FSHD-associated repeat.
Facioscapulohumeral muscular dystrophy (FSHD) is a relatively common autosomal dominant neuromuscular disorder. The gene for FSHD has recently been assigned to chromosome 4q35. Although abnormal mitochondrial and biochemical changes have been observed in FSHD, the molecular defect is unknown. In addition to the FSHD gene, the human muscle adenine nucleotide translocator gene (ANT1) is located on chromosome 4. Interestingly, biochemical studies recently showed a possible defect of ANT1. In order to evaluate the potential role of ANT1 in the etiology of FSHD, the human ANT1 gene was isolated by cosmid cloning and localized to 4q35, in the region containing the FSHD gene. However, in situ hybridization and physical mapping of somatic cell hybrids localized the ANT1 gene proximal to the FSHD gene. In addition, a polymorphic CA-repeat 5 kb upstream of the ANT1 gene was used as a marker in FSHD and Centre d'Etude du Polymorphisme Humain families to perform linkage analysis. These data together exclude ANT1 as the primary candidate gene for FSHD. The most likely order of the loci on chromosome 4q35 is cen-ANT1-D4S171-F11-D4S187-D4S163-D4S139-+ ++FSHD-tel.
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of inherited muscle disease following Duchenne and myotonic dystrophy. FSHD is initially characterized by an asymmetric, progressive weakness of the facial and pectoral girdle muscles. The disorder is inherited in an autosomal dominant fashion with nearly complete penetrance. FSHD results from a deletion of integral copies of a 3.3-kb tandem repeat unit on the long arm of chromosome 4 (D4Z4). A "short" EcoR1 fragment (< 35 kb) containing D4Z4 segregates with the disease, whereas the size of this polymorphic locus in the normal population ranges between 35 and 300 kb. The immediate proximity of the 3.3-kb tandem repeat to the telomere and its sequence similarity to constituitive heterochromatin suggest that this repeat, deleted in FSHD, lies in telomeric heterochromatin. This conclusion is further supported by the fact that, despite intense efforts over the past seven years, there have been no protein coding transcripts identified fr om this repeat sequence. Integral deletions of the heterochromatic D4Z4 repeat instead appear to disrupt the normal expression of adjacent genes, a phenomenon akin to position effect variegation in Drosophila and telomere silencing in yeast. The genes affected by the D4Z4 polymorphism have not been identified, as the 4qter region is rich in repetitive and pseudogene sequences. We are currently using the Affymetrix GeneChip system to examine large-scale differential gene expression in FSHD muscle tissue and myoblast cell lines. In addition, we have used the GeneChip system to examine the regulatory mechanism disrupted by deletions of the heterochromatic repeat D4Z4. Differential gene expression in yeast strains carrying telomeric half-YACs encompassing the FSHD region have been analysed in an effort to identify yeast homologues of genes involved in heterochromatin formation at the D4Z4 locus. A number of genes involved in DNA interstrand crosslink repair were found to be upregulated, perh aps unveiling the initial mutational mechanism in this disease. Thus, we will likely yield immense insight into both the regulatory and mutational mechanisms of the human disease FSHD as well as elucidate the primary cause of this disorder through microarray analysis.Exposure of cells to anticancer agents can result in altered gene expression. In general, only a single gene or a small number of genes are studied. To improve the efficiency and value of such experiments, we are interested in using DNA array technology to identify, on a genome-wide scale, drug-responsive genes which might serve both as surrogate markers for drug action and as future targets for drug development. As a means to establish this approach in our Centre we have carried out two exploratory projects. In the first project, we examined gene expression in p53 wild-type and mutant ovarian cell lines established from two patients with ovarian cancer who achieved a complete remission following treatment. Neither line can grow in vitro and were passaged as subcu...
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