A novel p.I141V mutation in the SCN4A gene caused a hyperpolarizing shift (-12.9 mV) in activation and increased window current, leading to a myotonic phenotype.
Does the p.I141V mutation in the SCN4A gene alter the electrophysiological properties of the Nav1.4 channel leading to myotonia?
A novel p.I141V mutation in the SCN4A gene causes a gain-of-function alteration in activation leading to a myotonic phenotype.
BACKGROUND: Mutations in SCN4A may lead to myotonia. METHODS: Presentation of a large family with myotonia, including molecular studies and patch clamp experiments using human embryonic kidney 293 cells expressing wild-type and mutated channels. RESULTS: In a large family with historic data on seven generations and a clear phenotype, including myotonia at movement onset, with worsening by cold temperature, pregnancy, mental stress, and especially after rest after intense physical activity, but without weakness, the phenotype was linked with the muscle sodium channel gene (SCN4A) locus, in which a novel p.I141V mutation was found. This modification is located within the first transmembrane segment of domain I of the Na(v)1.4 alpha subunit, a region where no mutation has been reported so far. Patch clamp experiments revealed a mutation-induced hyperpolarizing shift (-12.9 mV) of the voltage dependence of activation, leading to a significant increase (approximately twofold) of the window current amplitude. In addition, the mutation shifted the voltage dependence of slow inactivation by -8.7 mV and accelerated the entry to this state. CONCLUSIONS: We propose that the gain-of-function alteration in activation leads to the observed myotonic phenotype, whereas the enhanced slow inactivation may prevent depolarization-induced paralysis.
Petitprez et al. (Mon,) conducted a other in Myotonia. p.I141V mutation in SCN4A vs. Wild-type channels was evaluated on Voltage dependence of activation and slow inactivation. A novel p.I141V mutation in the SCN4A gene caused a hyperpolarizing shift (-12.9 mV) in activation and increased window current, leading to a myotonic phenotype.