Myotonic dystrophy (DM) is caused by either an untranslated CTG expansion in the 3′ untranslated region of the DMPK gene on chromosome 19 (dystrophia myotonica type 1 [DM1]), or an untranslated CCTG tetranucleotide repeat expansion in intron 1 of the ZNF9 gene on chromosome 3 (dystrophia myotonica type 2 [DM2]). RNA-binding proteins adhere to transcripts of the repeat expansions that accumulate in the nucleus, and a trans-dominant dysregulation of pre-mRNA alternative splicing has been demonstrated for several genes. In muscle from patients with DM1, altered insulin-receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the DM phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of the disease. We now demonstrate that comparable splicing abnormalities occur in DM2 muscle prior to the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions.
|Original language||English (US)|
|Number of pages||5|
|Journal||American Journal of Human Genetics|
|State||Published - Jun 2004|
Bibliographical noteFunding Information:
Support from National Institutes of Health (NIH) grant R01AR45653, Muscular Dystrophy Association USA, and the Hunter Research Fund (to T.C.) and support from University of Minnesota General Clinical Research Center grant MO1-RR00400, the Muscular Dystrophy Association USA, and NIH grant R01NS35870 (to L.P.W.R. and J.W.D.) is gratefully acknowledged. We are also very grateful to members of the MN-1 family and other DM-affected families, without whose involvement this work would have been impossible.