A204E mutation in Na(v)1.4 DIS3 exerts gain- and loss-of-function effects that lead to periodic paralysis combining hyper- with hypo-kalaemic signs

Periodic paralyses (PP) are characterized by episodic muscle weakness and are classified into the distinct hyperkalaemic (hyperPP) and hypokalaemic (hypoPP) forms. The dominantly-inherited form of hyperPP is caused by overactivity of Na(v)1.4 — the skeletal muscle voltage-gated sodium channel. Familial hypoPP results from a leaking gating pore current induced by dominant mutations in Na(v)1.4 or Ca(v)1.1, the skeletal muscle voltage-gated calcium channel. Here, we report an individual with clinical signs of hyperPP and hypokalaemic episodes of muscle paralysis who was heterozygous for the novel p.Ala204Glu (A204E) substitution located in one region of Na(v)1.4 poor in disease-related variations. A204E induced a significant decrease of sodium current density, increased the window current, enhanced fast and slow inactivation of Na(v)1.4, and did not cause gating pore current in functional analyses. Interestingly, the negative impact of A204E on Na(v)1.4 activation was strengthened in low concentration of extracellular K(+). Our data prove the existence of a phenotype combining signs of hyperPP and hypoPP due to dominant Na(v)1.4 mutations. The hyperPP component would result from gain-of-function effects on Na(v)1.4 and the hypokalemic episodes of paralysis from loss-of-function effects strengthened by low K(+). Our data argue for a non-negligible role of Na(v)1.4 loss-of-function in familial hypoPP.