A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis.
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.
Rojas
C V
CV
Department of Molecular Genetics, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Wang
J Z
JZ
Schwartz
L S
LS
Hoffman
E P
EP
Powell
B R
BR
Brown
R H
RH
D000595:Amino Acid Sequence; D000818:Animals; D002886:Chromosomes, Human, Pair 17; D004252:DNA Mutational Analysis; D004330:Drosophila; D004524:Eels; D005799:Genes, Dominant; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009132:Muscles / Q000502:physiology*; D010245:Paralyses, Familial Periodic / Q000235:genetics*; D010375:Pedigree; D011188:Potassium / Q000502:physiology; D051381:Rats; D016415:Sequence Alignment; D015222:Sodium Channels / Q000235:genetics*
D008565:Membrane Proteins; D015222:Sodium Channels; D011188:Potassium