Changing Channel

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Science  02 Aug 2002:
Vol. 297, Issue 5582, pp. 739
DOI: 10.1126/science.297.5582.739b

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy and is caused by expansion of an unstable CTG trinucleotide repeat in the 3′ untranslated region of the DM protein kinase gene. Healthy individuals have fewer than 40 CTG repeats in this gene, whereas patients with DM1 can have as many as thousands of repeats. One model of DM1 pathogenesis postulates that transcription of the DM1 allele produces pathogenic RNAs whose extended CUG tract disrupts critical nuclear events such as RNA splicing.

Provocative experimental support for the pathogenic RNA model is provided by Mankodi et al. and Charlet-B. et al., who report that aberrant splicing may account for the muscle membrane hyperexcitability (myotonia) that is a hallmark feature of DM. Studying skeletal muscle from a mouse model of DM1, as well as DM1 patients, the authors find that expression of expanded CUG repeats is accompanied by a reduction in transmembrane chloride conductance and by aberrant splicing of the pre-mRNA encoding ClC-1, a muscle-specific chloride channel previously implicated in myotonia. The splicing defect, which leads to reduced levels of the ClC-1 protein in the cell membrane, may be due to increased activity of a splicing regulator called CUG binding protein. — PAK

Mol. Cell10, 35, 45 (2002).

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