A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis

Nature. 1991 Dec 5;354(6352):387-9. doi: 10.1038/354387a0.


HYPERKALAEMIC periodic paralysis (HYPP) is an autosomal dominant disease that results in episodic electrical inexcitability and paralysis of skeletal muscle. Electrophysiological data indicate that tetrodotoxin-sensitive sodium channels from muscle cells of HYPP-affected individuals show abnormal inactivation. Genetic analysis of nine HYPP families has shown tight linkage between the adult skeletal muscle sodium channel alpha-subunit gene on chromosome 17q and the disease (lod score, z = 24; recombination frequency 0 = 0), strongly suggesting that mutations of the alpha-subunit gene cause HYPP. We sequenced the alpha-subunit coding region isolated from muscle biopsies from affected (familial HYPP) and control individuals by cross-species polymerase chain reaction-mediated complementary DNA cloning. We have identified an A----G substitution in the patient's messenger RNA that causes a Met----Val change in a highly conserved region of the alpha-subunit, predicted to be in a transmembrane domain. This same change was found in a sporadic case of HYPP as a new mutation. We have therefore discovered a voltage-gated channel mutation responsible for a human genetic disease.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chromosomes, Human, Pair 17
  • DNA Mutational Analysis
  • Drosophila
  • Eels
  • Genes, Dominant
  • Humans
  • Membrane Proteins / genetics
  • Molecular Sequence Data
  • Muscles / physiology*
  • Paralyses, Familial Periodic / genetics*
  • Pedigree
  • Potassium / physiology
  • Rats
  • Sequence Alignment
  • Sodium Channels / genetics*


  • Membrane Proteins
  • Sodium Channels
  • Potassium

Associated data

  • GENBANK/S67861
  • GENBANK/S67865
  • GENBANK/S68227
  • GENBANK/X57452
  • GENBANK/X57453
  • GENBANK/X57454
  • GENBANK/X57455
  • GENBANK/X62895
  • GENBANK/X62896
  • GENBANK/X62897