MUTATIONS IN THE HUMAN SKELETAL-MUSCLE CHLORIDE CHANNEL GENE (CLCN1) ASSOCIATED WITH DOMINANT AND RECESSIVE MYOTONIA-CONGENITA

Myotonia, defined as delayed relaxation of muscle after contraction, i s seen in a group of genetic disorders that includes autosomal dominan t myotonia congenita (Thomsen's disease) and autosomal recessive myoto nia congenita (Becker's disease). Both disorders are characterized ele ctrophysiologically by increased excitability of muscle fibers, reflec ted in clinical myotonia. These diseases are similar except that trans ient weakness is seen in patients with Becker's, but not Thomsen's dis ease. Becker's and Thomsen's diseases are caused by mutations in the s keletal muscle voltage-gated chloride channel gene (CLCN1). Genetic sc reening of a panel of 18 consecutive myotonia congenita (MC) probands for mutation in CLCN1 revealed that a novel Gln-68-Stop nonsense mutat ion predicts premature truncation of the chloride channel protein. Fou r previously reported mutations, Arg-894-stop, Arg-338-Gln, Gly-230-Gl u, and del 1437-1450, were also noted in our sample set. The Arg-338-G ln and Gly-230-Glu mutations were found in patients with different phe notypes from those of previous reports. Further study of the Arg-338-G ln and Gly-230-Glu alleles may shed light on variable modes of transmi ssion (dominant versus recessive) in different families. Physiologic s tudy of these mutations may lead to better understanding of the pathop hysiology of myotonia in these patients and of voltage-gated chloride channel structure/function relationships in skeletal muscles.