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From the Department of Human Genetics (F.-F. Wu), University of Pittsburgh, PA; Departments of Neurology (Drs. Takahashi and Cannon) and Neurobiology (Dr. Cannon), Massachusetts General Hospital, Harvard Medical School, Boston, MA; Neuromuscular Unit, Department of Neurological and Psychiatric Sciences (Drs. Pegoraro and Angelini), University of Padova, Italy; Division of Pediatrics (Dr. Colleselli), ULSS n.1 Belluno Agordo Cadore, O.C. di Belluno, Belluno, Italy; and the Research Center for Genetic Medicine (F.-F. Wu and Dr. Hoffman), Children’s National Medical Center, Washington, DC.
Address correspondence and reprint requests to Dr. Eric P. Hoffman, Research Center for Genetic Medicine, Children’s National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010; e-mail: ehoffman{at}childrens-research.org
OBJECTIVE: To identify the molecular and physiologic abnormality in familial myotonia with cold sensitivity, hypertrophy, and no weakness.
BACKGROUND: Sodium channel mutations were previously identified as the cause of several allelic disorders with varying combinations of myotonia and periodic paralysis. A three-generation family with dominant myotonia aggravated by cooling, but no weakness, was screened for mutations in the skeletal muscle sodium channel 
-subunit gene (SCN4A).
METHODS: Single-strand conformation polymorphism was used to screen all 24 exons of SCN4A and abnormal conformers were sequenced to confirm the presence of mutations. The functional consequence of a SCN4A mutation was explored by recording sodium currents from human embryonic kidney cells transiently transfected with an expression construct that was mutated to reproduce the genetic defect.
RESULTS: A three-generation Italian family with myotonia is presented, in which a novel SCN4A mutation (leucine 266 substituted by valine, L266V) is identified. This change removes only a single methylene group from the 1,836-amino-acid protein, and is present in a region of the protein previously not known to be critical for channel function (domain I transmembrane segment 5). Electrophysiologic studies of the L266V mutation showed defects in fast inactivation, consistent with other disease-causing SCN4A mutations studied to date. Slow inactivation was not impaired.
CONCLUSIONS: This novel mutation of the sodium channel indicates that a single carbon change in a transmembrane -helix of domain I can alter channel inactivation and cause cold-sensitive myotonia.
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