Efforts toward understanding the molecular basis of facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a frequency of 1 in 20,000. The report in 1992 of a DNA polymorphism that occurred both in familial and sporadic cases led to the pronouncement that the FSHD defect had been identified. Unfortunately, 2 years have passed without the isolation of a gene or definitive proof of the mutation. Over this time it has become clear that the region of the human genome containing the FSHD gene is a complex assemblage of mildly repetitive sequences that includes the suspected polymorphic fragment. We have employed molecular and cytogenetic techniques to initiate the structural analysis of terminal 4q35 in an effort to facilitate the isolation of the gene responsible for FSHD. As a result of these efforts and our inability to identify expressed sequences unique to 4q35 we have begun to consider alternate hypotheses for a molecular mechanism resulting in FSHD other than a simple coding sequence disruption.