Myotonia caused by mutations in the muscle chloride channel geneCLCN1

Abstract

Pure non‐syndromic, non‐dystrophic myotonia in humans is caused by mutations in the genes coding for the skeletal muscle sodium channel (SCN5A) or the skeletal muscle chloride channel (CLCN1) with similar phenotypes. Chloride‐channel myotonia can be dominant (Thomsen‐type myotonia) or recessive (Becker‐type myotonia). More than 60 myotonia‐causing mutations in the CLCN1 gene have been identified, with only a few of them being dominant. A common phenotype of dominant mutations is a dominant negative effect of mutant subunits in mutant‐WT heterodimers, causing a large shift of the steady‐state open probability voltage‐dependence towards more positive, unphysiological voltages. The study of the properties of disease causing mutations has helped in understanding the functional properties of the CLC‐1 channel that is part of a nine‐member gene family of chloride channels. The large body of knowledge obtained for CLC‐1 may also help to better understand the other CLC channels, three of which are also involved in genetic diseases. Hum Mutat 19:423–434, 2002.