Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution(1). It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness, Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark(2). We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)(6) repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)(8-13) in the 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) allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.