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Unequal Crossing-over in Unique PABP2 Mutations in Japanese Patients
A Possible Cause of Oculopharyngeal Muscular Dystrophy
Mika Nakamoto, MD, PhD;
Satoshi Nakano, MD, PhD;
Shingo Kawashima, MD, PhD;
Masafumi Ihara, MD;
Yo Nishimura, MD;
Akiyo Shinde, MD;
Akira Kakizuka, MD, PhD
Arch Neurol. 2002;59:474-477.
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)6GCA(GCG)3(GCA)3GCG
and (GCG)6(GCA)3(GCG)2(GCA)3GCG
alleles instead of the normal (GCG)6(GCA)3GCG allele.
These mutated alleles could be explained by the insertions or duplications
of (GCG)3GCA 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)3GCA 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.
From the Fourth Department, Osaka Bioscience Institute, Osaka (Drs
Nakamoto and Kakizuka), and the Departments of Neurology, Kyoto University
Faculty of Medicine, Kyoto (Drs Nakano, Kawashima, Ihara, and Shinde), and
Nishikobe Medical Center, Hyogo (Dr Nishimura), Japan. Dr Nakamoto is now
with the Department of Neurology, Emory University Graduate School of Arts
and Sciences, Atlanta, Ga; Dr Nakano, the Department of Neurology, Kansai
Medical University, Osaka, Japan; and Dr Kakizuka, Laboratory of Functional
Biology, Graduate School of Biostudies, Kyoto University.
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