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

The voltage dependent chloride channel CIC-1 stabilizes resting membrane potential in skeletal muscle. Mutations in the CIC-1 gene are responsible for both human autosomal recessive generalized myotonia and autosomal dominant myotonia congenita. To understand the tissue distribution and subcellular localization of CIC-1 and to evaluate its role in an animal model of myotonia, antibodies were raised against the carboxyl terminus of this protein. Expression of the 130-kDa CIC-1 protein is unique to skeletal muscle, consistent with its mRNA tissue distribution. Immunolocalization shows prominent CIC-1 antigen in the sarcolemma of both type I and II muscle fibers. Sarcolemma localization is confirmed by Western analysis of skeletal muscle subcellular fractions. The ADR myotonic mouse (phenotype ADR, genotype adr/adr), in which defective CIC-1 mRNA has been identified, is shown here to be absent in CIC-1 protein expression, whereas other skeletal muscle sarcolemma protein expression appears normal, Immunohistochemistry of skeletal muscle from ADR and other mouse models of human muscle disease demonstrate that the absence of CIC-1 chloride channel is a defect specific to ADR mice.