Hypokalemic periodic paralysis (HypoPP) is an inherited skeletal muscle ion channelopathy of CACNA1S or SCN4A characterized by recurrent episodes of weakness, often triggered by rest after exercise or by reduced K+ (carbohydrate ingestion, stress). Here, we describe a multigenerational family in whom a KCNA7 missense variant [c.834A>C (p.Arg278Ser)] co-segregated with susceptibility to recurrent attacks of weakness in association with hypokalemia as low as 1.3 mEq/L and a 40% decrement of the compound muscle action potential after exercise, suggesting an additional HypoPP gene. Arg278 is the outermost positively charged residue (R1) within the S4 transmembrane segment of the voltage-sensor domain of KV1.7, orthologous to the canonical patten of arginine missense mutations at R1 or R2 in S4 segments for HypoPP-mutant CaV1.1 and NaV1.4 channels. To determine the functional consequences of Arg278Ser, we expressed wild-type and mutant KV1.7 channels in Xenopus oocytes and HEK293 cells. Arg278Ser, but not wild-type KV1.7, generated an anomalous inwardly rectifying current at hyperpolarized membrane potentials that was nonselective Na+ or K+, consistent with the anomalous gating pore conductance that causes susceptibility to HypoPP. Other pathogenic variants of KCNA7 have previously been implicated only in inherited cardiac arrhythmias. Collectively, the genetic, structural and electrophysiological findings support KCNA7 Arg278Ser as a pathogenic variant underlying HypoPP and implicate KCNA7 as a disease gene for periodic paralysis, extending the established gating-pore mechanism of HypoPP to KV1.7.
Liaqat, K., Saha, G., Guo, S., Treat, K., Wu, F., Thahiem, S., Kincaid, J. C., Undiagnosed Disease Network,, Rubart-von der Lohe, M., Vetrini, F., Cannon, S., Conboy, E.
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