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

Dao W. Wang, Dorothy Vandecarr, Peter C. Ruben, Alfred L. George*, Paul B. Bennett

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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. Copyright (C) 1999 Federation of European Biochemical Societies.

Original languageEnglish (US)
Pages (from-to)231-234
Number of pages4
JournalFEBS Letters
Volume448
Issue number2-3
DOIs
StatePublished - Apr 9 1999

Keywords

  • Flecainide
  • Myotonia
  • SCN4A
  • Sodium channel

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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