ABSTRACT
FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology, edited by Meena Upadhyaya and David N.Cooper. © 2004 Garland/BIOS Scientific Publishers Limited, Abingdon.
16.1 Introduction
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy after Duchenne and myotonic dystrophy with an estimated prevalence of 1:20 000, resulting in severe disability in 15-20% of affected individuals. Clinical diagnosis of FSHD is based on the presence of a characteristic distribution of weakness in facial, proximal arm, and scapular musculature. EMG and muscle biopsy findings in FSHD are non-specific (Tawil and Griggs, 1997). FSHD is inherited in an autosomal dominant manner although as many as a third of cases have no family history and are the result of de novo mutations. The molecular rearrangements associated with the clinical phenotype of FSHD-deletions of integral numbers of 3.3 kb KpnI units on chromosome 4q35 (van Deutekom et al., 1993; Wijmenga et al., 1994; Upadhyaya et al., 1997), termed ‘D4Z4 repeats’, did not lead to the immediate identification of a single disease gene. Rather, extrapolating from studies in Drosophila and other organisms (Cattanach, 1974; Jaenisch et al., 1981; Tartof et al., 1984; Henikoff, 1994; Bedell et al., 1996), the position effect hypothesis (Winokur et al 1994) proposed cis-interactions between the subtelomeric region of 4q35 and a gene (or genes) lying centromeric to the D4Z4 repeats. In this model, a dominant negative effect occurs as a result of the D4Z4 deletions in FSHD, possibly by derepression of a silent gene(s) or maintenance of a gene(s) in a transcriptionally active state after expression should have been down-regulated. Such a model is consistent with the autosomal dominant nature of the FSHD mutation. Subsequently, it was hypothesized that the unconventional coding sequence in each repeat (has been termed DUX4) may be expressed in FSHD, but not control, myoblasts (Gabriels et al., 1999; Coppee et al., 2002). Moreover, recent studies have demonstrated the presence of beta-satellite repeats downstream of the D4Z4 repeats on the allele which is deleted in FSHD (Lemmers et al., 2002). This suggests that an additional parameter, perhaps related to locus-specific chromatin folding or binding of specific factors, plays a
role in the connection between the loss of D4Z4 repeats and the disease phenotype. While studies at the level of DNA sequence and chromatin organization on chromosome 4q35 proceed, we have pursued parallel studies in vitro to examine the effects of the molecular changes at the level of the muscle cell.
