Misregulation of alternative splicing causes pathogenesis in myotonic dystrophy.

Neslihan Martinez, Thomas A. Cooper

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Myotonic dystrophy (DM), the most common form of adult onset muscular dystrophy, affects skeletal muscle, heart, and the central nervous system (CNS). Mortality results primarily from muscle wasting and cardiac arrhythmias. There are two forms of the disease: DM1 and DM2. DM1, which constitutes 98% of cases, is caused by a CTG expansion in the 3' untranslated region (UTR) of the DMPK gene. DM2 is caused by a CCTG expansion in the first intron of the ZNF9 gene. RNA containing CUG- or CCUG-expanded repeats are transcribed but are retained in the nucleus in foci. Disease pathogenesis results primarily from a gain of function of the expanded RNAs, which alter developmentally regulated alternative splicing as well as pathways of muscle differentiation. The toxic RNA has been implicated in sequestration of splicing regulators and transcription factors thereby causing specific symptoms of the disease. Here we review the proposed mechanisms for the toxic effects of the expanded repeats and discuss the molecular mechanisms of splicing misregulation and disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)133-159
Number of pages27
JournalProgress in molecular and subcellular biology
Volume44
StatePublished - 2006
Externally publishedYes

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Myotonic Dystrophy
Alternative Splicing
Poisons
RNA
Muscles
Muscular Dystrophies
3' Untranslated Regions
Introns
Genes
Cardiac Arrhythmias
Skeletal Muscle
Transcription Factors
Central Nervous System
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Misregulation of alternative splicing causes pathogenesis in myotonic dystrophy. / Martinez, Neslihan; Cooper, Thomas A.

In: Progress in molecular and subcellular biology, Vol. 44, 2006, p. 133-159.

Research output: Contribution to journalArticle

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