A novel CLCN1 mutation: P480T in a Japanese family with Thomsen's myotonia congenita.

At least 50 disease-causing mutations in the skeletal muscle voltage-gated chloride channel gene (CLCN1), almost all of which originate from Caucasian families, have been identified. We investigated a Japanese family with Thomsen's myotonia congenita that included 16 affected individuals (8 men and 8 women) through five generations. Polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) screening of 11 members showed an aberrant conformer in exon 13 of CLCN1 complementary DNA (cDNA) in 8 affected and 1 unaffected members. By sequence analysis, we identified a C-to-A transition at nucleotide position 1438, resulting in a substitution of proline for threonine at amino acid position 480 (P480T), the same position of the original mutation (P480L) in Thomsen's disease. The P480T mutation was novel and absent in 100 normal controls. Seven of the 8 affected individuals were heterozygous; another, from affected parents, was homozygous. Clinically, myotonia in the homozygous patient was more severe than that in heterozygous patients, probably due to the gene dosage effect. On a long-train nerve-stimulation test at a rate of 3 Hz, M-wave responses in the homozygous patient showed marked decrement followed by recovery. In contrast, the heterozygous patients showed just a slight decrement or no changes, and none of 2 patients with myotonic muscular dystrophy or 2 normal controls revealed any decrement. Thus, the long-train nerve-stimulation test at a low stimulus frequency may be a useful tool to assess the disease-severity/genotype relationship in myotonia congenita.