Inactivation of muscle chloride channel by transposon insertion in myotonic mice

Abstract

MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes¹. Purely myotonic human diseases are dominant myotonia congenita (Thomsen) and recessive generalized myotonia (Becker), whereas myotonic dystrophy is a systemic disease. Muscle hyperexcitability was attributed to defects in sodium channels^2,3 and/or to a decrease in chloride conductance (in Becker's myotonia⁴ and in genetic animal models^5–10). Experimental blockage of Cl⁻ conductance (normally 70–85% of resting conductance in muscle11) in fact elicits myotonia^1,9. ADR (ref. 12) mice are a realistic animal model^{5–7,12–18} for recessive autosomal myotonia. In addition to Cl⁻ conductance⁵, many other parameters^6,12,16 are changed in muscles of homozygous animals. We have now cloned the major mammalian skeletal muscle chloride channel (C1C-1)¹⁹. Here wereport that in ADR mice a transposon of the ETn family^20–23 has inserted into the corresponding gene, destroying its coding potential for several membrane-spanning domains. Together with the lack of recombination between the Clc-1 gene and the adr locus, this strongly suggests a lack of functional chloride channels as the primary cause of mouse myotonia.