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

Abstract

HYPERKALAEMIC periodic paralysis (HYPP)1 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 inactivation2,3. Genetic analysis of nine HYPP families has shown tight linkage between the adult skeletal muscle sodium channel α-subunit gene on chromosome 17q and the disease (lod score, z = 24; recombination frequency 0 = 0)4–6, strongly suggesting that mutations of the a-subunit gene cause HYPP. We sequenced the a-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 α-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.

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Rojas, C., Wang, J., Schwartz, L. et al. A Met-to-Val mutation in the skeletal muscle Na+ channel α-subunit in hyperkalaemic periodic paralysis. Nature 354, 387–389 (1991). https://doi.org/10.1038/354387a0

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