Copyright © 2004 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 74, Issue 6, 1309-1313, 1 June 2004
doi:10.1086/421528
Report
Insulin Receptor Splicing Alteration in Myotonic Dystrophy Type 2
R.S. Savkur1, A.V. Philips1, T.A. Cooper1, J.C. Dalton2, M.L. Moseley2, 4, L.P.W. Ranum2, 4 and J.W. Day2, 3, 
, 
1 Department of Pathology, Baylor University, Houston
2 Institute of Human Genetics, University of Minnesota, Minneapolis
3 Department of Neurology, University of Minnesota, Minneapolis
4 Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis
Address for correspondence and reprints: Dr. John W. Day, Professor of Neurology, Institute of Human Genetics, MMC 206, University of Minnesota, 420 Delaware Street, Minneapolis, MN 55455.Abstract
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.
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