Functional consequences of a domain 1/S6 segment sodium channel mutation associated with painful congenital myotonia

An unusual form of painful congenital myotonia is associated with a novel S CN4A mutation causing a valine to methionine substitution in the domain 1/S 6 segment of the skeletal muscle sodium channel. We studied the functional characteristics of this mutant allele using a recombinant channel to gain u nderstanding about the nature of the biophysical defect responsible for thi s unique phenotype. When expressed heterologously in a cultured mammalian c ell 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-i nactivating 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. Flecainid e, 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 dem onstrate 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. (C) 1999 Federati on of European Biochemical Societies.