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Functional consequences of a domain 1/S6 segment sodium channel mutation associated with painful congenital myotonia
Author(s) -
Wang Dao W,
VanDeCarr Dorothy,
Ruben Peter C,
George Alfred L,
Bennett Paul B
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)00338-5
Subject(s) - myotonia , sodium channel , flecainide , mutant , mutation , gating , sodium channel blocker , chemistry , endocrinology , medicine , methionine , biophysics , sodium , pharmacology , microbiology and biotechnology , biology , biochemistry , amino acid , gene , organic chemistry , myotonic dystrophy , atrial fibrillation
An unusual form of painful congenital myotonia is associated with a novel SCN4A mutation causing a valine to methionine substitution in the domain 1/S6 segment of the skeletal muscle sodium channel. We studied the functional characteristics of this mutant allele using a recombinant channel to gain understanding about the nature of the biophysical defect responsible for this unique phenotype. When expressed heterologously in a cultured mammalian cell line (tsA201), the mutant channel exhibits subtle defects in its gating properties similar, but not identical, to other myotonia‐producing sodium channel mutations. The main abnormalities are the presence of a small non‐inactivating current that occurs during short test depolarizations, a shift in the voltage‐dependence of channel activation to more negative potentials, and a slowing of the time course of recovery from inactivation. Flecainide, a potent sodium channel blocker previously reported to benefit patients affected by this form of myotonia, effectively inhibits the abnormal sodium current associated with expression of the mutant channel. Our findings demonstrate the unique pattern of sodium channel dysfunction associated with a D1/S6 myotonia‐producing sodium channel mutation, and provide a mechanism for the beneficial effects of flecainide in this setting.