A polyalanine antibody for the diagnosis of oculopharyngeal muscular dystrophy and polyalanine-related diseases

Abstract

Eighteen severe human diseases have so far been associated with trinucleotide repeat expansions coding for either polyalanine (encoded by a GCN repeat tract) or polyglutamine (encoded by a CAG repeat tract).  Among them, oculopharyngeal muscular dystrophy (OPMD), spinocerebellar ataxia type-3 (SCA3), and Huntington’s disease (HD) are late-onset autosomal-dominant disorders characterized by the presence of intranuclear inclusions (INIs).  We have previously identified the OPMD causative mutation as a small expansion (from 2 in normal to 7 in disease) of a GCG repeat tract in the PABPN1 gene.  In addition, -1 ribosomal frameshifting has been reported to occur in expanded CAG repeat tracts in the ATXN3 (SCA3) and HTT (HD) genes, resulting in the translation of a hybrid CAG/GCA repeat tract and the production of a polyalanine-containing peptide.  Previous studies on OPMD suggest that polyalanine-induced toxicity is very sensitive to the dosage and length of the alanine stretch.  Here we report the characterization of a polyclonal antibody that selectively recognizes pathological expansions of polyalanine in PABPN1.  Furthermore, our antibody also detects the presence of alanine proteins in INIs of SCA3 and HD patient samples.