Copyright © 2004 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 74, Issue 5, 793-804, 1 May 2004
doi:10.1086/383590
Review Article
Myotonic Dystrophy: RNA Pathogenesis Comes into Focus
Laura P.W. Ranum1, 2, 
, 
and John W. Day1, 3
1 Institute of Human Genetics, University of Minnesota, Minneapolis
2 Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis
3 Department of Neurology, University of Minnesota, Minneapolis
Address for correspondence and reprints: Laura P. W. Ranum, Ph.D., MMC 206, 420 Delaware Street S.E., Minneapolis, MN 55455Abstract
Myotonic dystrophy (DM)—the most common form of muscular dystrophy in adults, affecting 1/8,000 individuals—is a dominantly inherited disorder with a peculiar and rare pattern of multisystemic clinical features affecting skeletal muscle, the heart, the eye, and the endocrine system. Two genetic loci have been associated with the DM phenotype: DM1, on chromosome 19, and DM2, on chromosome 3. In 1992, the mutation responsible for DM1 was identified as a CTG expansion located in the 3′ untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). How this untranslated CTG expansion causes myotonic dystrophy type 1(DM1) has been controversial. The recent discovery that myotonic dystrophy type 2 (DM2) is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. We discuss the pathogenic mechanisms that have been proposed for the myotonic dystrophies, the clinical and molecular features of DM1 and DM2, and the characterization of murine and cell-culture models that have been generated to better understand these diseases.
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