Functional consequences of chloride channel gene (CLCN1) mutations causingmyotonia congenita

Objective: To determine the functional consequences of missense mutations w ithin the skeletal muscle chloride channel gene CLCN1 that cause myotonia c ongenita. Background: Myotonia congenita is a genetic muscle disease associ ated with abnormalities in the skeletal muscle voltage-gated chloride (ClC- 1) channel. In order to understand the molecular basis of this inherited di sease, it is important to determine the physiologic consequences of mutatio ns found in patients affected by it. Methods: The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell volt age-clamp technique to functionally express and physiologically characteriz e five CLCN1 mutations. Results: The I329T mutation shifted the voltage dep endence of open probability of ClC-1 channels to the right by 192 mV, and t he R338Q mutation shifted it to the right by 38 mV. In addition, the I329T ClC-1 channels deactivated to a lesser extent than normal at negative poten tials. The V165G, F167L, and F413C ClC-1 channels also shifted the voltage dependence of open probability, but only by + 14 to + 20 mV. Conclusions: T he functional consequences of these mutations form the physiologic argument that these are disease-causing mutations and could lead to myotonia congen ita by impairing the ability of the skeletal muscle voltage-gated chloride channels to maintain normal muscle excitability. Understanding of genetic a nd physiologic defects may ultimately lead to better diagnosis and treatmen t of patients with myotonia congenita.