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Functional consequences of chloride channel gene (CLCN1) mutations causing myotonia congenita

Jie Zhang, MS, Saïd Bendahhou, PhD, Michael C. Sanguinetti, PhD and Louis J. Ptáek, MD

From the Department of Neurology (J. Zhang and Dr. Ptáek), Department of Human Genetics (Dr. Ptáek), Program in Neuroscience (J. Zhang, Drs. Sanguinetti, and Ptáek), Department of Internal Medicine (Dr. Sanguinetti), and the Howard Hughes Medical Institute (Drs. Bendahhou and Ptáek), University of Utah, Salt Lake City, UT.

Address correspondence and reprint requests to Dr. L.J. Ptáek, Howard Hughes Medical Institute, University of Utah, Building 533, Room 4420, 15N 2030 East, Salt Lake City, UT 84112-5331.

OBJECTIVE: To determine the functional consequences of missense mutations within the skeletal muscle chloride channel gene CLCN1 that cause myotonia congenita.

BACKGROUND: Myotonia congenita is a genetic muscle disease associated with abnormalities in the skeletal muscle voltage-gated chloride (ClC-1) channel. In order to understand the molecular basis of this inherited disease, it is important to determine the physiologic consequences of mutations found in patients affected by it.

METHODS: The authors used a mammalian cell (human embryonic kidney 293) expression system and the whole-cell voltage-clamp technique to functionally express and physiologically characterize five CLCN1 mutations.

RESULTS: The I329T mutation shifted the voltage dependence of open probability of ClC-1 channels to the right by 192 mV, and the 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 potentials. The V165G, F167L, and F413C ClC-1 channels also shifted the voltage dependence of open probability, but only by +14 to +20 mV.

CONCLUSIONS: The functional consequences of these mutations form the physiologic argument that these are disease-causing mutations and could lead to myotonia congenita by impairing the ability of the skeletal muscle voltage-gated chloride channels to maintain normal muscle excitability. Understanding of genetic and physiologic defects may ultimately lead to better diagnosis and treatment of patients with myotonia congenita.

Key words: Chloride channel—Mutation—Function—Myotonia—Neuromuscular diseases—Electrophysiology—Genetics

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