[Myotonia and cardiac conduction defects in myotonic dystrophy and defect in ion channels]

Abstract

Myotonic dystrophy (DM), the most common hereditary muscle disease in adults, is caused by the unstable genomic expansion of simple sequence repeats. This disease is characterized by myotonia and various multisystemic complications, most commonly those of the cardiac, endocrine, and central nervous systems. The cardiac abnormalities, especially cardiac conduction defects, significantly contribute to morbidity and mortality in DM patients. Therefore, understanding the pathophysiology of cardiac conduction defects in DM is important. The pathomechanism of DM has been thoroughly investigated. The mutant RNA transcripts containing the expanded repeat give rise to a toxic gain-of-function by perturbing splicing factors in the nucleus, leading to the misregulation of alternative pre-mRNA splicing. In particular, several studies, including ours, have shown that myotonia is caused by alternative splicing of the CLCN1 gene coding the voltage-gated chloride channel in skeletal muscle through an "RNA-dominant mechanism". Since the aberrantly spliced isoform does not seem to form a functional channel, the feature of skeletal muscle in DM can be interpreted as a "channelopathy" caused by reduced chloride channel protein. Similarly, we recently identified a misregulation of alternative splicing in an ion channel gene which is known to be responsible for arrhythmic disease showing Mendelian inheritance. Here, we review the cardiac manifestation and RNA-dominant mechanism of DM, and discuss the possible pathophysiology of cardiac conduction defects by referring to hereditary arrhythmic diseases, such as long QT syndrome and Brugada syndrome.