Barbara Weiffenbach

The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: Implications for a role of chromatin structure in the pathogenesis of the disease

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant form of muscular dystrophy. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. Recently, a probe was identified that detects anEcoRI fragment length polymorphism which segregates with the disease in most FSHD families. Within theEcoRI fragment lies a tandem array of 3.2 kb repeats. In several familial cases and four independent sporadic FSHD mutations, the variation in size of theEcoRI fragment was due to a decrease in copy number of the 3.2 kb repeats. To gain further insight into the relationship between the tandem array and FSHD, a single 3.2 kb repeat unit was characterized. Fluorescencein situ hybridization (FISH) demonstrates that the 3.2 kb repeat cross-hybridizes to several regions of heterochromatin in the human genome. In addition, DNA sequence analysis of the repeat reveals a region which is highly homologous to a previously identified family of heterochromatic repeats, LSau. FISH on interphase chromosomes demonstrates that the tandem array of 3.2 kb repeats lies within 215 kb of the 4q telomere. Together, these results suggest that the tandem array of 3.2 kb repeats, tightly linked to the FSHD locus, is contained in heterochromatin adjacent to the telomere. In addition, they are consistent with the hypothesis that the gene responsible for FSHD may be subjected to position effect variegation because of its proximity to telomeric heterochromatin.

Extreme variability of expression in monozygotic twins with FSH muscular dystrophy.

We describe monozygotic twins who are either discordant or show extreme variability in the expression of facioscapulohumeral muscular dystrophy (FSHD). One twin was severely incapacitated by FSHD. The asymptomatic twin demonstrated equivocal facial weakness on physical examination, but no difference on quantitative myometry when compared with normal controls. High-resolution cytogenetic analysis showed no chromosomal abnormalities. Five polymorphic 4q35 markers known to be linked to FSHD showed identical RFLP patterns, indicating that submicroscopic chromosomal rearrangement is unlikely. We conclude that this set of twins represents an extreme case of variability in the expression of the FSHD gene.

Framework multipoint map of the long arm of human Chromosome 4 and telomeric localization of the gene for FSHD

Mapping the long arm of Chromosome (Chr) 4 has assumed medical relevance with the establishment of linkage of facioscapulohumeral muscular dystrophy (FSHD) to distal 4q markers. We have constructed a multipoint linkage map using DNA markers that map to the long arm of Chr 4. Segregation data were collected for 17 DNA markers on the multigenerational CEPH mapping families, and data for one marker were taken from the published CEPH database. Genotypic information for six of these markers was also collected from a set of 24 families that exhibited inheritance of FSHD. Multipoint analyses allowed us to construct a map of 12 loci, connecting two previously separate linkage groups. Significant sexspecific differences in recombination were found for some genetic intervals. Four loci from the distal region of this map showed linkage with FSHD. A map using these terminal markers gave the strongest support for FSHD in the most distal position over all other possible positions.