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

Collaborative Research, Inc. Waltham, Massachusetts 02154.
Nature Genetics (Impact Factor: 29.35). 07/1993; 4(2):165-9. DOI: 10.1038/ng0693-165
Source: PubMed


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.

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    • "The mechanism by which D4Z4 mitotically rearranges is well studied in de novo kindreds with FSHD. Although germline mosaicism has been only sporadically reported in studies of FSHD (Griggs et al. 1993; Weiffenbach et al. 1993), almost half of de novo FSHD cases arise through a mitotic rearrangement, either in the unaffected carrier parent of an affected nonmosaic child or in the affected individual (van der Maarel et al. 2000). In these mosaic individuals, there seems to be a relationship between the severity of the disease and the combination of the residual repeat size and the proportion of cells carrying the disease allele. "

    Preview · Article · Apr 2005 · The American Journal of Human Genetics
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    • "In the human genome the 3.3-kb repeats are present on several chromosomes other than 4q—specifically, on the short arms of acrocentric chromosomes, 1q12 and 10qter—as shown by in situ hybridization experiments (Deidda et al. 1995; Winokur et al. 1996). The spreading of KpnI repeat sequences on human chromosomes generates artifacts in the interpretation of DNA analysis in normal subjects and in FSHD patients, since (a) multiple EcoRI fragments are observed after hybridization with p13E-11 probe and (b) time-consuming linkage analysis with 4q35 and 10qter markers is required to assign the chromosomal origin of the alleles (Weiffenbach et al. 1993; Deidda et al. 1994). We found that the 10qter locus shows a high degree of homology with the 4q35 locus, as shown by restriction mapping and in situ hybridization experiments (Deidda et al. 1995). "
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    ABSTRACT: Physical mapping and in situ hybridization experiments have shown that a duplicated locus with a structural organization similar to that of the 4q35 locus implicated in facioscapulohumeral muscular dystrophy is present in the subtelomeric portion of 10q. We performed sequence analysis of the p13E-11 probe and of the adjacent KpnI tandem-repeat unit derived from a 10qter cosmid clone and compared our results with those published, by other laboratories, for the 4q35 region. We found that the sequence homology range is 98%-100% and confirmed that the only difference that can be exploited for differentiation of the 10qter from the 4q35 alleles is the presence of an additional BlnI site within the 10qter KpnI repeat unit. In addition, we observed that the high degree of sequence homology does facilitate interchromosomal exchanges resulting in displacement of the whole set of BlnI-resistant or BlnI-sensitive KpnI repeats from one chromosome to the other. However, partial translocations escape detection if the latter simply relies on the hybridization pattern from double digestion with EcoRI/BlnI and with p13E-11 as a probe. We discovered that the restriction enzyme Tru9I cuts at both ends of the array of KpnI repeats of different chromosomal origins and allows the use of cloned KpnI sequences as a probe by eliminating other spurious fragments. This approach coupled with BlnI digestion permitted us to investigate the structural organization of BlnI-resistant and BlnI-sensitive units within translocated chromosomes of 4q35 and 10q26 origin. A priori, the possibility that partial translocations could play a role in the molecular mechanism of the disease cannot be excluded.
    Full-text · Article · Aug 1998 · The American Journal of Human Genetics
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    • "Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant, progressive neuromuscular disorder with an estimated prevalence of 1–5 per 100000 (Lunt and Harper 1991). Genetic and physical mapping strategies have identified a polymorphic 3.3 kb tandem repeat (D4Z4) on human chromosome 4q35 that is tightly linked to FSHD (Wijmenga et al. 1992; Passos-Bueno et al. 1993; Upadhyaya et al. 1993; Weiffenbach et al. 1993; Wright et al. 1993; Wijmenga et al. 1994). In unaffected individuals the EcoRI fragment containing D4Z4 varies in size between approximately 50 and 320 kb, while in familial cases of FSHD linked to chromosome 4 the disease co-segregates with a fragment below this range in size. "
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    ABSTRACT: The D4Z4 locus is a polymorphic tandem repeat sequence on human chromosome 4q35. This locus is implicated in the neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD). The majority of sporadic cases of FSHD are associated with de novo DNA deletions within D4Z4. However, it is still not known how this rearrangement causes FSHD. Although the repeat contains homeobox sequences, despite exhaustive searching, no transcript from this locus has been identified. Therefore, it has been proposed that the deletion may invoke a position effect on a nearby gene. In order to try to understand the role of the D4Z4 repeat in this disease, we decided to investigate its conservation in other species. In this study, the long-range organisation and localisation of loci homologous to D4Z4 were investigated in primates using Southern blot analysis, pulsed field gel electrophoresis and fluorescence in situ hybridisation. In humans, probes to D4Z4 identify, in addition to the 4q35 locus, a closely related tandem repeat at 10qter and many related repeat loci mapping to the acrocentric chromosomes; a similar pattern was seen in all the great apes. In Old World monkeys, however, only one locus was detected in addition to that on the homologue of human chromosome 4, suggesting that the D4Z4 locus may have originated directly from the progenitor locus. The finding that tandem arrays closely related to D4Z4 have been maintained at loci homologous to human chromosome 4q35-qter in apes and Old World monkeys suggests a functionally important role for these sequences.
    Full-text · Article · Oct 1996 · Chromosoma
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