MYOTONIC-DYSTROPHY - EVIDENCE FOR A POSSIBLE DOMINANT-NEGATIVE RNA MUTATION

The trinucleotide expansion mutation causing myotonic dystrophy is in the 3' untranslated region of a protein kinase gene, The molecular mec hanisms by which the expanded repeat causes the clinically variable an d multisystemic disease, myotonic dystrophy, are not understood. It ha s 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. Her e we use muscle biopsies from classical adult-onset myotonic dystrophy patients to study the accumulation of transcripts from both the norma l acid expanded DM kinase genes in patient muscle, and compare the res ults to normal and myopathic controls. We found relatively small decre ases of DM kinase RNA in the total RNA pool from muscle; however, thes e reductions were not disease specific. Analysis of poly(A)(+) RNA sho wed dramatic decreases of both the mutant and normal DM kinase RNAs, a nd these changes were disease-specific. Our findings are consistent wi th a novel molecular pathogenetic mechanism far myotonic dystrophy: bo th the normal and expanded DM kinase genes are transcribed in patient muscle, but the abnormal expansion-containing RNA has a dominant effec t on RNA metabolism by preventing the accumulation of poly(A)(+) RNA. The ability of the expansion mutation to alter accumulation of poly(A) (+) RNA in trans suggests that myotonic dystrophy may be the first exa mple of a dominant-negative mutation manifested at the RNA level.