ABSENCE OF THE SKELETAL-MUSCLE SARCOLEMMA CHLORIDE CHANNEL CLC-1 IN MYOTONIC MICE

The voltage dependent chloride channel CIC-1 stabilizes resting membra ne potential in skeletal muscle. Mutations in the CIC-1 gene are respo nsible for both human autosomal recessive generalized myotonia and aut osomal dominant myotonia congenita. To understand the tissue distribut ion and subcellular localization of CIC-1 and to evaluate its role in an animal model of myotonia, antibodies were raised against the carbox yl terminus of this protein. Expression of the 130-kDa CIC-1 protein i s unique to skeletal muscle, consistent with its mRNA tissue distribut ion. Immunolocalization shows prominent CIC-1 antigen in the sarcolemm a of both type I and II muscle fibers. Sarcolemma localization is conf irmed by Western analysis of skeletal muscle subcellular fractions. Th e ADR myotonic mouse (phenotype ADR, genotype adr/adr), in which defec tive CIC-1 mRNA has been identified, is shown here to be absent in CIC -1 protein expression, whereas other skeletal muscle sarcolemma protei n expression appears normal, Immunohistochemistry of skeletal muscle f rom ADR and other mouse models of human muscle disease demonstrate tha t the absence of CIC-1 chloride channel is a defect specific to ADR mi ce.