TY - JOUR
T1 - A new mutation in a family with cold-aggravated myotonia disrupts Na+ channel inactivation
AU - Wu, F. F.
AU - Takahashi, M. P.
AU - Pegoraro, E.
AU - Angelini, C.
AU - Colleselli, P.
AU - Cannon, S. C.
AU - Hoffman, E. P.
PY - 2001/4/10
Y1 - 2001/4/10
N2 - 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.
AB - 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.
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U2 - 10.1212/WNL.56.7.878
DO - 10.1212/WNL.56.7.878
M3 - Article
C2 - 11294924
AN - SCOPUS:0035836631
SN - 0028-3878
VL - 56
SP - 878
EP - 884
JO - Neurology
JF - Neurology
IS - 7
ER -