Profound misregulation of muscle-specific gene expression in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder c haracterized by an insidious onset and progressive course. The disease has a frequency of about 1 in 20,000 and is transmitted in an autosomal dominan t fashion with almost complete penetrance. Deletion of an integral number o f tandemly arrayed 3.3-kb repeat units (D4Z4) on chromosome 4q35 is associa ted with FSHD hut otherwise the molecular basis of the disease and its path ophysiology remain obscure. Comparison of mRNA populations between appropri ate cell types can facilitate identification of genes relevant to a particu lar biological or pathological process. in this report, we have compared mR NA populations of FSHD and normal muscle. Unexpectedly, the dystrophic musc le displayed profound alterations in gene expression characterized by sever e underexpression or overexpression of specific mRNAs, intriguingly, many o f the deregulated mRNAs are muscle specific. Our results suggest that a glo bal misregulation of gene expression is the underlying basis for FSHD, dist inguishing it from other forms of muscular dystrophy. The experimental appr oach used here is applicable to any genetic disorder whose pathogenic mecha nism is incompletely understood.