Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant inherited disease with an estimated European prevalence of 1 per 100,000. OPMD is a late-onset disorder characterized by progressive ptosis, dysphagia and proximal limb weakness. A mutation in the „poly(A) binding protein nuclear1“(PABPN1)-gene was identified to be responsible for the disease. The characteristic mutation is an expansion of a (GCG)6 trinucleotide repeat to a length of (GCG)8-13. An ultrastructural hallmark of OPMD is the presence of intranuclear tubular inclusions in muscle fibers with an outer diameter of 8.5 nm. These inclusions contain PABPN1. In this study molecular genetic examinations were performed in 6 patients with clinically and electron microscopically verified OPMD. Sequence analysis revealed a mutation in the PABPN1-gene in all 6 cases. Interestingly, one of the mutations differs from the classical expansion of the (GCG)6 tract to (GCG)8-13. In patient number 5 a (GCA)2GCG insertion was identified following the (GCG)6 sequence. This insertion has not been described before. Conclusions on the mechanism leading to the mutation causative for OPMD may be drawn from this mutation detected in patient 5. It lets the unequal crossing over mechanism appear to be more plausible than the polymerase slippage model.Fragment analysis was performed with the RT-PCR products of the mRNA isolated from the patients muscle biopsies. In all 6 cases fragments of the mutated and of the normal alleles were detectable. The integrals of fluorescence signals which were detected in fragment analysis were used to determine the ratio between the amount of RT-PCR products of mutated versus normal alleles. In 5 cases, a higher amount of RT-PCR products of the mutated allele was found. To some degree the ratios between the amount of RT-PCR products of mutated versus normal alleles correlated with weakness of the muscles from which the biopsies had been taken.The results of this study might help to elucidate some open questions in the pathogenesis of OPMD. The mutation found in patient 5 gives a hint on the mechanism which leads to the mutation in the PABPN1-gene. Furthermore the results suggest that allelic transcription might have an influence on the clinical picture of the disease.
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