SHORT GCG EXPANSIONS IN THE PABP2 GENE CAUSE OCULOPHARYNGEAL MUSCULAR-DYSTROPHY

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adu lt-onset disease with a world-wide distribution(1). It usually present s in the sixth decade with progressive swallowing difficulties (dyspha gia), eyelid drooping (ptosis) and proximal limb weakness, Unique nucl ear filament inclusions in skeletal muscle fibres are its pathological hallmark(2). We isolated the poly(A) binding protein 2 gene (PABP2) f rom a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manu script submitted). A (GCG)(6) repeat encoding a polyalanine tract loca ted at the N terminus of the protein was expanded to (GCG)(8-13) in th e 144 OPMD families screened, More severe phenotypes were observed in compound heterozygotes for the (GCG)(9) mutation and a (GCG)(7) allele that is found in 2% of the population, whereas homozygosity for the ( GCG)(7) allele leads to autosomal recessive OPMD. Thus the (GCG)(7) al lele is an example of a polymorphism which can act either as a modifie r of a dominant phenotype or as a recessive mutation. Pathological exp ansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.