A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis.
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Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH Jr
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.
- PubMed ID
- 1659668 [ View in PubMed]
- Abstract
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.