Key result
Novel CLCN1 P480T mutation linked to Thomsen's myotonia congenita with homozygosity driving more severe myotonia.
Why the study?
Most known disease-causing mutations in the skeletal muscle chloride channel gene CLCN1 originate from Caucasian families, with limited data on mutations in other populations such as Japanese families with Thomsen's myotonia congenita.
Observational (n=16)
Identified a novel P480T mutation in the CLCN1 gene causing Thomsen's myotonia congenita in a Japanese family, demonstrating that a low-frequency long-train nerve-stimulation test can assess the disease-severity/genotype relationship.
May support targeted genetic testing in familial myotonia; hypothesis-generating for homozygosity-severity links pending larger studies.
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.
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Sasaki et al. (2001) conducted an observational in Thomsen's myotonia congenita (n=16). P480T mutation in the CLCN1 gene vs. Unaffected family members and normal controls was evaluated on Clinical severity and M-wave response on long-train nerve-stimulation test. A novel P480T mutation in the CLCN1 gene was identified in a Japanese family with Thomsen's myotonia congenita, with homozygosity resulting in more severe clinical and electrophysiological myotonia.
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