A204E mutation in Nav1.4 DIS3 exerts gain- and loss-of-function effects that lead to periodic paralysis combining hyper- with hypo-kalaemic signs

Abstract

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 Nav1.4 — the skeletal muscle voltage-gated sodium channel. Familial hypoPP results from a leaking gating pore current induced by dominant mutations in Nav1.4 or Cav1.1, 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 Nav1.4 poor in disease-related variations. A204E induced a significant decrease of sodium current density, increased the window current, enhanced fast and slow inactivation of Nav1.4, and did not cause gating pore current in functional analyses. Interestingly, the negative impact of A204E on Nav1.4 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 Nav1.4 mutations. The hyperPP component would result from gain-of-function effects on Nav1.4 and the hypokalemic episodes of paralysis from loss-of-function effects strengthened by low K+. Our data argue for a non-negligible role of Nav1.4 loss-of-function in familial hypoPP.

A novel gain‐of‐function mutation in SCN5A responsible for multifocal ectopic Purkinje‐related premature contractions

“…This mutation in both channels shares some biophysical properties regarding the leftward shift of steady‐state activation, the hyperpolarization of the window current and the increase in the probability of being within this window current. Nevertheless, differently than Kokunai et al (2018), we did not observe any modification of the amplitude, nor the steady‐state inactivation of the current generated by A204E mutant channels, compared to WT. Considering the high similarity between both skeletal and cardiac Na + channels' regulation, function, and biophysics, these divergences have no explanation.…”

“…The A204E variant has also been reported in the skeletal‐muscle Na + channel, Na v 1.4, in a case of periodic paralysis (Kokunai et al, 2018), leading to a complex phenotype of gain‐ and loss‐of‐function in HEK cells. This mutation in both channels shares some biophysical properties regarding the leftward shift of steady‐state activation, the hyperpolarization of the window current and the increase in the probability of being within this window current.…”

Hypokalaemic periodic paralysis with a charge-retaining substitution in the voltage sensor

“…If this were the case, then we propose the HypoPP phenotype may be from another gene (one-third of clinically definite HypoPP patients do not have an identified mutation in CACNA1S or SCN4 ) or in a non-coding region of CACNA1S or SCN4A . Atypical forms of HypoPP that are unusual because of coexisting myotonia or HyperPP have mixed gain-of-function and loss-of-function defects ( Sugiura et al , 2003 ; Kokunai et al , 2018 ; Luo et al , 2018 ). Alternative pathomechanisms are less apparent for HypoPP mutations of Ca V 1.1 without gating pore currents.…”

Inherited Neuromuscular Disorders: Which Role for Serum Biomarkers?

“…As far as hypo- and hyperkaliemic periodic paralyses (PP) are concerned, serum diagnostic supportive criteria are constituted by K + concentrations <3.5 and >4.5 mEq/L during weakness attacks, respectively [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. Raised CK may be present too [ 74 , 75 ].…”