Myotonic dystrophy is an autosomal dominant degenerative disorder affecting muscle fibres but with a complex phenotype including cataracts, cardiac conduction abnormalities, insulin resistance, sleep disorders, testicular atrophy, and frontal balding (Box 7.15). The molecular basis for these seemingly unrelated manifestations involves altered RNA processing as a result of interactions between the repeat expansions in the encoded RNA, and specific RNA binding proteins. A change in the activity or level of these RNA binding proteins alters RNA splicing (Box 1.20) such that particular isoforms are expressed, with organ-specific consequences.
Expansion of (CTG)n repeats in the 3' untranslated region (UTR) of the dystrophia myotonica-protein kinase (DMPK) gene at 19q13.3 was found to cause myotonic dystrophy in 1992 (Brook et al. 1992; Fu et al. 1992; Mahadevan et al. 1992). Affected individuals were found to have from 50 to several thousand copies of CTG repeats. It was subsequently recognized that a proportion of patients did not have this repeat and had some clinically distinct features, for example proximal rather than distal muscle weakness and involvement of type 2 rather than type 1 muscle fibres. These patients were classified as having myotonic dystrophy type 2 (DM2; OMIM 602668) and in 2001 the underlying defect was found to be a (CCTG)n repeat expansion comprising on average 5000 repeats in intron 1 of the zinc finger protein 9 (ZNF9) gene at 3q21 (Liquori et al. 2001).
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