Background: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant muscle disease with a worldwide distribution. Recent findings reveal the genetic basis of this disease to be mutations in the polyA binding-protein 2 (PABP2) gene that involve short expansions of the GCG trinucleotide repeat encoding a polyalanine tract. The underlying mechanism causing the triplet-expansion mutation in PABP2 remains to be elucidated, although the DNA slippage model is thought to be a plausible explanation of that.
Methods and results: We analyzed PABP2 using polymerase chain reaction analysis and DNA sequencing in Japanese patients with pathologically confirmed OPMD, and found mutated (GCG)(6)GCA(GCG)(3)(GCA)(3)GCG and (GCG)(6)(GCA)(3)(GCG)(2)(GCA)(3)GCG alleles instead of the normal (GCG)(6)(GCA)(3)GCG allele. These mutated alleles could be explained by the insertions or duplications of (GCG)(3)GCA and (GCG)(2)(GCA)(3), respectively, but not by the simple expansion of GCG repeats. The clinical features of our patients were compatible with those of other Japanese patients carrying PABP2 that encodes a polyalanine tract of the same length, but were not compatible with those of Italian patients.
Conclusions: The mutated alleles identified in our Japanese patients with OPMD were most likely due to duplications of (GCG)(3)GCA and (GCG)(2)(GCA)(3) but not simple expansions of the GCG repeats. Therefore, unequal crossing-over of 2 PABP2 alleles, rather than DNA slippage, is probably the causative mechanism of OPMD mutations. All mutations that have been reported in patients with OPMD so far can be explained with the mechanism of unequal crossing-over. On the other hand, comparison of the clinical features of our patients with those of other patients in previous reports suggests that specific clinical features cannot be attributed to the length of the polyalanine tract per se.