SPLICING ABNORMALITIES IN MYOTONIC DYSTROPHIES

Myotonic dystrophy of type 1 (DM1) is one of the most common muscular dystrophy in adults characterized by progressive muscle wasting and weakness, myotonia, cardiac conduction defects, alteration in cognitive functions as well as several other multisystemic symptoms. DM1 is an autosomal dominant inherited disease caused by an unstable CTG expansion ranging from ~50 to more than 1,000 repeats in the 3’ non-coding region of the DMPK gene. Expression of DMPK RNAs with expanded CUG repeats supports a toxic RNA gain-of-function as a pathologic mechanism for DM1. A similar or common mechanism may also be involved in DM type 2 that is caused by CCTG expansion in the first intron of the CNP (ZNF9) gene and shares similar clinical features with DM1 disease. In both myotonic dystrophies, nuclear accumulation of pathogenic CUG/CCUGexp-RNAs alters the activities of the RNA binding proteins such as MBNL1 and CUG-BP1 that leads to alternative splicing mis-regulation of a numerous of transcripts in DM tissues and ultimately, to clinical features of the disease. An overview of the DM splicing mis-regulation will be presented, with focus on mis- regulation of the BIN1 mRNA. In muscle, BIN1 plays an important role in tubular invaginations of the plasma membrane and is required for biogenesis of T-tubules, which are specialized membrane structures essential for excitation-contraction coupling. BIN1 splicing mis-regulation in DM patients due to MBNL1 loss-of-function results in the expression of an inactive form of BIN1 deprived of phosphoinositide-binding and membrane-tubulating activities. Reproducing similar BIN1 mis-splicing defect in the muscles of wild type mice is sufficient to promote T-tubule alterations and muscle strength decrease, suggesting that alteration of BIN1 splicing may contributes to muscle weakness, a prominent feature in DM.