Mutations in the CLCN1 gene leading to myotonia congenita Thomsen and generalized myotonia Becker

Autosomal dominant inherited myotonia congenita Thomsen (MC) and autosomal recessive generalized myotonia Becker (GM) are non-dystropic muscle disorders in which the symptom myotonia is based on an increased excitability of the muscle fiber membrane due to a reduced sarcolemmal chloride conductance. Affected individuals exhibit myotonic muscle stiffness in all skeletal muscles and a transient muscle weakness is particularly pronounced in the arms and hands of probands with the disorder GM. Recently we have shown linkage of the disorders MC and GM to the gene CLCN1 coding for the skeletal muscle chloride channel on chromosome 7 in German families. In addition we presented data supporting the hypothesis that GM is a genetically homogeneous disorder. Data are presented about an extended screen for mutations in the CLCN1 gene for our MC and GM population. We identified mainly missense mutations leading to altered amino acid codons. The previously described F413C mutation is by far the most common mutation for GM and is found in one family only (P480L, G482R, R496S). In addition we found 5{prime} donor and 3{prime} acceptor splice site mutations at various intron-exon boundaries, as well as a deletion mutation of 14 bp in exon 13. This deletion mutation is themore » second most common mutation in the GM population with a frequency of 8%. So far we have not determined sites of predominance of mutations in the CLCN1 gene, which could give us more insight into the regions critical for the function of the channel and the fact that the mutations in the gene may lead to dominant and recessive inheritance.« less