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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DOI: https://doi.org/10.1038/354387a0
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