title: Unequal crossing-over in unique PABP2 mutations in Japanese patients: a possible cause of oculopharyngeal muscular dystrophy.
abstract: 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.
  
  
  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.
authors.affiliation: Laboratory of Functional Biology, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Nakamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakano
authors.forename: Shingo
authors.initials: S
authors.lastname: Kawashima
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Yo
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Akiyo
authors.initials: A
authors.lastname: Shinde
authors.forename: Akira
authors.initials: A
authors.lastname: Kakizuka
mesh_terms: D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D003433:Crosses, Genetic; D004251:DNA Transposable Elements; D005260:Female; D020440:Gene Duplication; D006801:Humans; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics
chemical_list: D004251:DNA Transposable Elements; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins