A204E mutation in Nav1.4 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 weaknessand are classified into the distinct hyperkalaemic (hyperPP) and hypokalaemic (hypoPP) forms. The dominantly-inherited form of hyperPP is caused by overactivity of Nav1.4— the skeletal muscle voltage-gated sodium channel. Familial hypoPP results from a leaking gating pore current induced by dominant mutations in Nav1.4or Cav1.1, the skeletal muscle voltage-gated calcium channel. Here, we report an individual with clinical signs of hyperPP and hypokalaemic episodes of muscle paralysiswho was heterozygous for the novel p.Ala204Glu (A204E) substitution located in one region of Nav1.4poor in disease-related variations. A204E induced a significant decrease of sodium current density, increased the window current, enhanced fast and slow inactivation of Nav1.4, and did not cause gating pore current in functional analyses. Interestingly, the negative impact of A204E on Nav1.4activation 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 Nav1.4mutations. The hyperPP component would result from gain-of-function effects on Nav1.4and the hypokalemic episodes of paralysis from loss-of-function effects strengthened by low K+. Our data argue for a non-negligible role of Nav1.4loss-of-function in familial hypoPP.