Markov and Eyring Modeling Predict Differential Contributions of Homologous Mutations in Hypokalemic Periodic Paralysis to Skeletal Muscle Fiber Excitability

Abstract

Hypokalemic periodic paralysis is caused by mutations in the S4 region of voltage-gated sodium or calcium channels found in skeletal muscle. These mutations elicit a non-canonical omega current observed as a proton- or cationic leak through the voltage sensor domain in these channels. S4 mutations also produce defects in channel activation and inactivation. Here, we compared the impact of gating defects for homologous S4:R2 hNaV1.4 mutations on the excitability of muscle fibers. For domain I, R222G was identified in an index family as the clinical outcome of this mutation has not previously been described.