A new mutation in a family with cold-aggravated myotonia disrupts Na+ channel inactivation

F. F. Wu, M. P. Takahashi, E. Pegoraro, C. Angelini, P. Colleselli, S. C. Cannon, E. P. Hoffman

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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 α-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 α-helix of domain I can alter channel inactivation and cause cold-sensitive myotonia.

Original languageEnglish (US)
Pages (from-to)878-884
Number of pages7
Issue number7
StatePublished - Apr 10 2001

ASJC Scopus subject areas

  • Clinical Neurology


Dive into the research topics of 'A new mutation in a family with cold-aggravated myotonia disrupts Na+ channel inactivation'. Together they form a unique fingerprint.

Cite this