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

The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in t he 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 skelet al muscle sodium channel Lu subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers f rom a patient heterozygous for Arg-672-->Gly displayed depolarization and w eakness in low-potassium extracellular solution. Slowing and smaller size o f action potentials were suggestive of excitability of the wild-type channe l population only. Heterologous expression of the two sodium channel mutati ons 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 smal l action potentials suggested a low channel protein density. The alteration s 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 cr subunit of skeletal muscle is responsible for HypoPP-2 which do es not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease ca used by enhanced channel inactivation and current reduction showing no myot onia.