PMID: 7543316Apr 1, 1995Paper

Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation

Human Molecular Genetics
J WangE P Hoffman

Abstract

The trinucleotide expansion mutation causing myotonic dystrophy is in the 3' untranslated region of a protein kinase gene. The molecular mechanisms by which the expanded repeat causes the clinically variable and multisystemic disease, myotonic dystrophy, are not understood. It has been particularly difficult to rationalize the dominant inheritance with the fact that the expansion mutation lies outside of the protein-encoding gene elements, and should not be translated into protein. Here we use muscle biopsies from classical adult-onset myotonic dystrophy patients to study the accumulation of transcripts from both the normal and expanded DM kinase genes in patient muscle, and compare the results to normal and myopathic controls. We found relatively small decreases of DM kinase RNA in the total RNA pool from muscle; however, these reductions were not disease specific. Analysis of poly(A)+ RNA showed dramatic decreases of both the mutant and normal DM kinase RNAs, and these changes were disease-specific. Our findings are consistent with a novel molecular pathogenetic mechanism for myotonic dystrophy: both the normal and expanded DM kinase genes are transcribed in patient muscle, but the abnormal expansion-containing RNA has a domi...Continue Reading

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