共查询到20条相似文献,搜索用时 15 毫秒
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Eugénie Ansseau Dalila Laoudj-Chenivesse Aline Marcowycz Alexandra Tassin Céline Vanderplanck Sébastien Sauvage Marietta Barro Isabelle Mahieu Axelle Leroy India Leclercq Véronique Mainfroid Denise Figlewicz Vincent Mouly Gillian Butler-Browne Alexandra Belayew Frédérique Coppée 《PloS one》2009,4(10)
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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. 相似文献
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K D Mathews K A Mills E P Bosch V V Ionasescu K R Wiles K H Buetow J C Murray 《American journal of human genetics》1992,51(2):428-431
Fasioscapulohumeral muscular dystrophy (FSHD) has recently been localized to 4q35. We have studied four families with FSHD. Linkage to the 4q35 probes D4S163, D4S139, and D4S171 was confirmed. We found no recombinants helpful in detailed localization of the FSHD gene. Two of our families include males with a rapidly progressive muscle disease that had been diagnosed, on the basis of clinical features, as Duchenne muscular dystrophy. One of these males is available for linkage study and shares the haplotype of his FSHD-affected aunt and cousin. 相似文献
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Hanel ML Sun CY Jones TI Long SW Zanotti S Milner D Jones PL 《Differentiation; research in biological diversity》2011,81(2):107-118
Facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) is a candidate gene for mediating FSHD pathophysiology, however, very little is known about the endogenous FRG1 protein. This study uses immunocytochemistry (ICC) and histology to provide insight into FRG1's role in vertebrate muscle development and address its potential involvement in FSHD pathophysiology. In cell culture, primary myoblast/myotube cultures, and mouse and human muscle sections, FRG1 showed distinct nuclear and cytoplasmic localizations and nuclear shuttling assays indicated the subcellular pools of FRG1 are linked. During myoblast differentiation, FRG1's subcellular distribution changed dramatically with FRG1 eventually associating with the matured Z-discs. This Z-disc localization was confirmed using isolated mouse myofibers and found to be maintained in adult human skeletal muscle biopsies. Thus, FRG1 is not likely involved in the initial assembly and alignment of the Z-disc but may be involved in sarcomere maintenance or signaling. Further analysis of human tissue showed FRG1 is strongly expressed in arteries, veins, and capillaries, the other prominently affected tissue in FSHD. Overall, we show that in mammalian cells, FRG1 is a dynamic nuclear and cytoplasmic protein, however in muscle, FRG1 is also a developmentally regulated sarcomeric protein suggesting FRG1 may perform a muscle-specific function. Thus, FRG1 is the only FSHD candidate protein linked to the muscle contractile machinery and may address why the musculature and vasculature are specifically susceptible in FSHD. 相似文献
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This paper investigates the nuclear localization of human telomeres and, specifically, the 4q35 subtelomere mutated in facioscapulohumeral dystrophy (FSHD). FSHD is a common muscular dystrophy that has been linked to contraction of D4Z4 tandem repeats, widely postulated to affect distant gene expression. Most human telomeres, such as 17q and 17p, avoid the nuclear periphery to reside within the internal, euchromatic compartment. In contrast, 4q35 localizes at the peripheral heterochromatin with 4p more internal, generating a reproducible chromosome orientation that we relate to gene expression profiles. Studies of hybrid and translocation cell lines indicate this localization is inherent to the distal tip of 4q. Investigation of heterozygous FSHD myoblasts demonstrated no significant displacement of the mutant allele from the nuclear periphery. However, consistent association of the pathogenic D4Z4 locus with the heterochromatic compartment supports a potential role in regulating the heterochromatic state and makes a telomere positioning effect more likely. Furthermore, D4Z4 repeats on other chromosomes also frequently organize with the heterochromatic compartment at the nuclear or nucleolar periphery, demonstrating a commonality among chromosomes harboring this subtelomere repeat family. 相似文献
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Cisca Wijmenga SaraT. Winokur GeorgeW. Padberg Mette I. Skraastad Michael R. Altherr John J. Wasmuth Jeffrey C. Murray Marten H. Hofker Rune R. Frants 《Human genetics》1993,92(2):198-203
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 upsstream 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. 相似文献
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Bosnakovski D Xu Z Gang EJ Galindo CL Liu M Simsek T Garner HR Agha-Mohammadi S Tassin A Coppée F Belayew A Perlingeiro RR Kyba M 《The EMBO journal》2008,27(20):2766-2779
Facioscapulohumeral muscular dystrophy (FSHD) is caused by an unusual deletion with neomorphic activity. This deletion derepresses genes in cis; however which candidate gene causes the FSHD phenotype, and through what mechanism, is unknown. We describe a novel genetic tool, inducible cassette exchange, enabling rapid generation of isogenetically modified cells with conditional and variable transgene expression. We compare the effects of expressing variable levels of each FSHD candidate gene on myoblasts. This screen identified only one gene with overt toxicity: DUX4 (double homeobox, chromosome 4), a protein with two homeodomains, each similar in sequence to Pax3 and Pax7. DUX4 expression recapitulates key features of the FSHD molecular phenotype, including repression of MyoD and its target genes, diminished myogenic differentiation, repression of glutathione redox pathway components, and sensitivity to oxidative stress. We further demonstrate competition between DUX4 and Pax3/Pax7: when either Pax3 or Pax7 is expressed at high levels, DUX4 is no longer toxic. We propose a hypothesis for FSHD in which DUX4 expression interferes with Pax7 in satellite cells, and inappropriately regulates Pax targets, including myogenic regulatory factors, during regeneration. 相似文献
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J. R. Gilbert J. M. Stajich M. C. Speer J. M. Vance C. S. Stewart L. H. Yamaoka F. Samson M. Fardeau T. G. Potter A. D. Roses M. A. Pericak-Vance 《American journal of human genetics》1992,51(2):424-427
Facioscapulohumeral muscular dystrophy (FSHD) has been localized to the 4q35-qter region of chromosome 4. Linkage analyses of two polymorphic markers from the region, D4S139 and D4S163, have been carried out using four large multigenerational FSHD families. The results indicate that both markers are closely linked to FSHD, with D4S139 being the closest proximal marker to FSHD. 相似文献
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High-resolution mapping of mouse Chromosome 8 identifies an evolutionary chromosomal breakpoint 总被引:3,自引:0,他引:3
Prabhjit K. Grewal Daniel J. Bolland Laura Carim Todd Jane E. Hewitt 《Mammalian genome》1998,9(8):603-607
The central region of mouse Chromosome (Chr) 8, containing the myodystrophy (myd) locus, is syntenic with human Chr 4q28-qter. The human neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD)
maps to Chr 4q35, and myd has been proposed as a mouse homolog of FSHD. We have employed a comparative mapping approach to investigate this relationship
further by extending the mouse genetic map of this region. We have ordered 12 genes in a single cross, 8 of which have human
homologs on 4q28-qter. The results confirm a general relationship between the most distal genes on human 4q and the most proximal
genes in the mouse 8 syntenic region. Despite chromosomal rearrangements of syntenic groups in this region, conservation of
gene order is maintained between the group of genes in the human telomeric region of 4q35 and MMU8. Furthermore, this conserved
telomeric HSA4q35 syntenic group maps proximal to the myd mutation and is flanked by genes with homologs on HSA8p22. At the proximal boundary of the MMU8 linkage group we have identified
a single 300-kb YAC containing the genes Frgl and Pcml, which have human homologs on 4q35 and 8p22, respectively. Thus, this YAC spans an evolutionary chromosomal breakpoint. As
well as providing clues about chromosomal evolution, this map of the FSHD syntenic mouse region should prove invaluable in
the isolation of candidate genes for this disease.
Received: 20 January 1998 / Accepted: 10 April 1998 相似文献