Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current

TLDR

The pathomechanism of familial hypokalemic periodic paralysis remains unclear despite known DHPR voltage‑sensor mutations. We identified two SCN4A voltage‑sensor mutations (Arg‑672→His and Arg‑672→Gly) in five HypoPP families lacking DHPR defects, and functional assays showed a left‑shifted inactivation curve, reduced current density, and lower channel protein levels, establishing SCN4A as the gene responsible for HypoPP‑2, a disorder clinically indistinguishable from DHPR‑HypoPP but without myotonia.

Abstract

The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor. In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672→His and →Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel α subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers from a patient heterozygous for Arg-672→Gly displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wild-type channel population only. Heterologous expression of the two sodium channel mutations revealed a 10-mV left shift of the steady-state fast inactivation curve enhancing inactivation and a sodium current density that was reduced even at potentials at which inactivation was removed. Decreased current and small action potentials suggested a low channel protein density. The alterations are decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels particularly at sustained membrane depolarization. The results prove that SCN4A, the gene encoding the sodium channel α subunit of skeletal muscle is responsible for HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease caused by enhanced channel inactivation and current reduction showing no myotonia.