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D. Rivera, J. C. Zenteno; Apparent Mitotic Instability of the Oculopharingeal Muscular Dystrophy Mutation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2808.
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© ARVO (1962-2015); The Authors (2016-present)
Oculopharingeal muscular dystrophy (OPMD) is an autosomal dominant disease caused by an expansion of the GCG triplet in the first exon of the PABPN1 gene, from a normal number of 6 to an abnormal number of 8 to 13 repeats. The main clinical features are adult onset and progressive ptosis, dysphagia, and limb weakness. To date there is no a clear genotype-phenotype correlation in OPMD and contrasting with other triplet expansion-related diseases, the OPMD mutation has been shown to be mitotically and meiotically stable through successive generations. In this work we describe two OPMD patients which presented 2 expanded PABPN1 alleles besides the normal PABPN1 allele and their clinical manifestations.
Two patients with OPMD were included in the study. Signs and symptoms were recorded for each patient. Molecular analysis consisted in DNA extraction from peripheral blood leucocytes, PCR amplification and allele specific cloning and sequencing of PABPN1 exon 1. Several individual alleles were cloned in order to establish an approximate of the allele frequencies.
One subject had a (GCG)9 expanded allele, a normal (GCG)6 allele and another expanded allele, (GCG)8 in a frequency of 12%. The other patient presented a (GCG)11 expanded allele, a normal (GCG)6 allele, and a second expanded allele (GCG)10, in a frequency of 9%. Age of onset and clinical features in these to patients were not different from those observed in OPMD subjects carrying one expanded PABPN1 allele.
Two different expanded alleles were found in two unrelated patients with OPMD. This finding suggests mosaicism for the OPMD mutation, possibly arising from mitotic instability of the expanded triplet. This finding has not been previously described in OPMD, possibly due to the fact that allele-specific cloning/sequencing are not routinely performed for genetic characterization of OPMD subjects. The clinical picture of these patients was not different from the usual clinical OPMD manifestations. The study of a more numerous group of OPMD patients using the allele-specific cloning/sequencing technique, would be needed to confirm this observation.
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