Inheritance of three distinct muscle chloride channel gene (CLCN1) mutations in a single recessive myotonia congenita family.

Abstract

Myotonia congenita is an inherited disorder of skeletal muscle membrane excitability that stems from diminished activity of the sarcolemmal voltage-gated chloride channel. The syndrome may be transmitted by either an autosomal dominant (Thomsen's disease) or recessive (recessive generalized myotonia, Becker's myotonia) mode of inheritance, [1] and the molecular genetic basis of both forms is linked to mutations in the skeletal muscle chloride channel gene (CLCN1, 7q35). This gene encodes a member of the ClC family of voltage-gated chloride channels and is believed to form multimeric complexes of subunits each consisting of 10 to 12 transmembrane domains. Although the disease is reported to be rare, there exists striking allelic heterogeneity with more than 25 known mutations in CLCN1. [2] Many patients with recessive generalized myotonia (RGM) exhibit compound heterozygosity with the inheritance of different maternal and paternal alleles. This high degree of genotype variability may help explain individual variability in disease severity. Here we report the unusual occurrence of a single family, segregating three distinct CLCN1 mutations resulting in two distinct compound genotypes in affected offspring. The proband is a 20-year-old woman with western European ancestry, presenting with a lifelong history of muscle stiffness. The patient's mother noted advanced muscular development at …