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 dominant effect 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 example of a dominant-negative mutation manifested at the
RNA level.