Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel

Abstract

Mutations in the skeletal muscle sodium channel gene (SCN4A) have been described in paramyotonia congenita (PMC) and hyperkalaemic periodic paralysis (HPP). We have found two mutations in SCN4A which affect regions of the sodium channel not previously associated with a disease phenotype. Furthermore, affected family members display an unusual mixture of clinical features reminiscent of PMC, HPP and of a third disorder, myotonia congenita (MC). The highly variable individual expression of these symptoms, including in some cases apparent non-penetrance, implies the existence of modifying factors. Mutations in SCN4A can produce a broad range of phenotypes in muscle diseases characterized by episodic abnormalities of membrane excitability.

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

“…8 Only a few individuals with rare mutations are clinically asymptomatic even though they are obligate carriers or show myotonic bursts on EMG. 9,10 De novo mutations have not yet been reported.…”

Congenital Myasthenic Syndromes - Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction

“…Dominant gain-of-function mutations in this gene cause hyperkalemic periodic paralysis (Ptacek et al, 1991), paramyotonia congenita (McClatchey et al, 1992;Ptacek et al, 1992), potassium-aggravated myotonia (Lerche et al, 1993), and hypokalemic periodic paralysis type 2 (Bulman et al, 1999). On the other hand, loss-of-function mutations cause a CMS.…”

Why are there so few resistance–associated mutations in insecticide target genes?

“…, an alanine-to-threonine replacement in the human SCN4A channel causes paramyotonia congenita, a disorder associated with decreased kinetics of sodium-channel inactivation (McClatchey et al 1992;Yang et al 1994). The same replacement in a mouse neuronal sodium channel produces the jolting phenotype (Kohrman et al 1996).…”