Mapping the facioscapulohumeral muscular dystrophy gene is complicated by 4q35 recombination events
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.
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The American Journal of Human Genetics 04/2005; 76(3):375-86. DOI:10.1086/428361 · 10.99 Impact Factor
- "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. "
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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). "
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.The American Journal of Human Genetics 08/1998; 63(1):181-90. DOI:10.1086/301906 · 10.99 Impact Factor
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- "For Duchenne muscular dystrophy (DMD), it has been shown that the frequency of cases resulting from germinal mosaicism depends on the site of the deletion in the dystrophin gene (Passos-Bueno et al. 1992). Somatic mosaicism has been previously reported for FSHD (Griggs et al. 1993; Weiffenbach et al. 1993), but its frequency is still unknown. It would be of interest to assess whether the mosaicism detected in peripheral blood in the propositus' mothers from the present study is also present in other tissues, in particular in skeletal muscle. "
ABSTRACT: A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been localized at 4q35. Subsequently, it was found that probe p13E-11 detects a polymorphic EcoRI fragment, usually > 28 kb, in normal individuals, whereas in sporadic and familial FSHD cases, an EcoRI fragment, usually < 28 kb, was found. Although these findings have been amply confirmed, several aspects are as yet either controversial or unsolved. In the present investigation, 34 Brazilian FSHD families were studied at the clinical and the molecular level for the following purposes: to assess the frequency of new mutations and their effect on estimates of biological fitness, to characterize FSHD-associated EcoRI fragments detected with probe p13E-11 in familial--as compared with isolated--FSHD cases, and to assess whether anticipation occurs in multigenerational families. Results from our study suggest that new mutations are apparently frequent for FSHD and may account for at least one-third of the cases, that somatic mosaicism may not be rare, and that biological fitness appeared to be reduced in FSHD, ranging from 0.6 to 0.82 by different estimates, with no difference in sexes. Interestingly, the size of the new EcoRI fragment is apparently smaller in more severely affected isolated patients. Moreover, the age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggests that anticipation occurs for FSHD in the majority of the families.The American Journal of Human Genetics 02/1995; 56(1):99-105. · 10.99 Impact Factor