Abstract
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterised by proximal muscle weakness, ptosis and swallowing difficulty. The causative genetic abnormality is an expansion consisting of 2–7 additional base triplets in a repeat sequence in exon 1 of the PABPN1 (PABP2) gene and results in an increase in length of the polyalanine tract in the PABPN1 protein from 10 to 12–17 residues. The expansions are stable through meiosis and mitosis suggesting a different mechanism of mutation from that of most other triplet repeat mutations. Most reports describe OPMD expansions as consisting of multiples of a GCG sequence. However, some studies have detected GCA interspersions. We have analysed 86 OPMD patients with a PABPN1 gene expansion, including three compound heterozygotes, and have identified 13 different types of expansion mutation, six of which contain GCA and GCG and almost all of which are consistent with a mutational mechanism of unequal recombination.
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References
Brais B (2003) Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. Cytogenet Genome Res 100(1–4):252–260
Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, et al (1998) Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet 18:164–167
Brown LY, Brown SA (2004) Alanine tracts: the expanding story of human illness and trinucleotide repeats. Trends Genet 20:51–58
Eichler EE, Holden JJ, Popovich BW, Reiss AL, Snow K, Thibodeau SN, Richards CS, Ward PA, Nelson DL (1994) Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet 8:88–94
Hill ME, Creed GA, McMullan TF, Tyers AG, Hilton-Jones D, Robinson DO, Hammans SR (2001) Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain 124:522–526
Nakamoto M, Nakano S, Kawashima S, Ihara M, Nishimura Y, Shinde A, Kakizuka A (2002) Unequal crossing over in unique PABP2 mutations in Japanese patients: a possible cause of oculopharyngeal muscular dystrophy. Arch Neurol 59:474–477
Scacheri PC, Garcia C, Herbert R, Hofman EP (1999) Unique PABP2 mutations in “Cajuns” suggest multiple founders of oculopharyngeal muscular dystrophy in populations with French ancestry. Am J Med Genet 86:477–481
Schober R, Kress W, Grahmann F, Kellermann S, Baum P, Gunzel S, Wagner A (2001) Unusual triplet repeat expansion associated with neurogenic changes with oculopharyngeal muscular dystrophy. Neuropathology 21:45–52
Van der Sluijs BM, Engelen BG van, Hoefsloot LH (2003) Oculopharyngeal muscular dystrophy due to a small duplication in the PABPN1 gene. Hum Mutat 21:553
Warren ST (1997) Polyalanine expansion in synpolydactyly might result from unequal crossing-over of HOXD13. Science 275(5298):408–409
Acknowledgements
The authors thank all patients and clinicians who sent samples for analysis to the Wessex Regional Genetics Laboratory, in particular Dr. John Winer and Professor Adrian Williams.
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Robinson, D.O., Hammans, S.R., Read, S.P. et al. Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism. Hum Genet 116, 267–271 (2005). https://doi.org/10.1007/s00439-004-1235-2
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DOI: https://doi.org/10.1007/s00439-004-1235-2