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

• Published in: Neurology Vol. 53; no. 9; p. 1932
• Main Authors: Bulman, D E, Scoggan, K A, van Oene, M D, Nicolle, M W, Hahn, A F, Tollar, L L, Ebers, G C
• Format: Journal Article
• Language: English
• Published: United States 10.12.1999
• Subjects: Adult; Amino Acid Sequence - genetics; Amino Acid Substitution - genetics; Arginine - genetics; Electromyography; Histidine - genetics; Humans; Hypokalemic Periodic Paralysis - diagnosis; Hypokalemic Periodic Paralysis - genetics; Male; Molecular Sequence Data; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Phenotype; Polymorphism, Single-Stranded Conformational; Sodium Channels - genetics
• ISSN: 0028-3878
• DOI: 10.1212/wnl.53.9.1932

To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor alpha1-subunit gene (CACNA1S). Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified. Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle alpha1-sodium channel gene (SCN4A) for a mutation in our family. 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. The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel genie 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.