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

Neurology. 1999 Dec 10;53(9):1932-6. doi: 10.1212/wnl.53.9.1932.


Objective: 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).

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 alpha1-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 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • NAV1.4 Voltage-Gated Sodium Channel
  • SCN4A protein, human
  • Sodium Channels
  • Histidine
  • Arginine