CLCN1

CLCN1 is a human gene that encodes the voltage-gated chloride channel ClC-1. The protein is predominantly expressed in skeletal muscle and forms a homodimer, with each subunit contributing a separate chloride pore. ClC-1 is voltage-dependent and contributes to the resting sarcolemmal chloride conductance, helping stabilize the muscle membrane potential and facilitate rapid repolarization after contraction.

Disruption of ClC-1 function reduces chloride conductance (gCl) in skeletal muscle, increasing membrane excitability and leading to myotonia, the delayed relaxation of muscles following voluntary contraction. The result is decreased muscle relaxation after use and stiffness that can improve with repeated activity.

Genetic disorders: Mutations in CLCN1 cause myotonia congenita, a skeletal-muscle channelopathy. Two classic forms are Thomsen disease (autosomal dominant) and Becker disease (autosomal recessive). Mutations are diverse, including missense, nonsense, splice-site, and frameshift changes, with a range of clinical severities. Diagnosis typically combines clinical evaluation, electromyography showing myotonic discharges, and genetic testing for CLCN1 variants. In some cases non-muscle involvement is minimal, and phenotypes may vary in onset and severity.

Genetics and research: The CLCN1 gene is located on chromosome 7q31.1. Animal models, such as CLCN1-deficient mice, reproduce myotonia and are used to study pathophysiology and therapeutic approaches. Treatment is generally symptomatic and may include physical therapy; medications such as mexiletine can reduce myotonia by decreasing membrane excitability.