Article abstract—

Objectives: To identify the disease-causing mutation and its molecular consequence for a clinically distinct type of myotonic myopathy. Backgrounds:— The authors encountered a unique myotonic disorder of early onset in a 37-year-old man and his 47-year-old sister.

Methods: After examining known loci of inherited myotonic disorders, the authors looked for mutations within the CLCN1 gene using single strand conformation polymorphism and direct sequencing. To investigate the disease mechanism, reverse transcriptase PCR analyses of total RNA were performed.

Results: In the proband and his affected sister, two novel mutations comprising a compound heterozygous state in the CLCN1 gene were identified: 1) a base (G) insertion in exon 7 generating a premature termination codon (fs289X) in the D5 domain, and 2) a C-to-T substitution in exon 23 resulting in a missense mutation (P932L). These mutations accompanied a clinical phenotype that is distinguishable from recessive myotonia congenita by progressive generalized muscle weakness, severe distal muscle atrophy, joint contractures, high serum creatine kinase levels, and conspicuous myopathic changes on muscle histopathology. Reverse transcriptase PCR analyses detected only the P932L mutant mRNA in skeletal muscle, suggesting that the fs289X mRNA is degraded rapidly.

Conclusions: These data suggest that fs289X is a null mutation, rendering the patients with the compound heterozygous genotype of fs289X/P932L to exclusively express P932L homomeric channels that may have caused the “dystrophic” phenotype.