A novel sodium channel mutation in a family with hypokalemic periodic paralysis

Objective: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease s not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha(1)-subunit gene (CACNA1S). Background: Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified. Methods: Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha(1)-sodium channel gene (SCN4A) for a mutation in our family. Results: SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing. Conclusions: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel gene CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.