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.
Similar content being viewed by others
References
Gamstorp, I. Acta paediatrica 45, 657–658 (1956).
Lehmann-Horn, F., Iaizzo, P. A., Hatt, H. & Franke, C. Eur. J. Physiol. 418, 297–299 (1991).
Cannon, S. C., Brown, R. H. & Corey, D. P. Neuron 6, 619–625 (1991).
Fontaine, B. et al. Science 250, 1000–1002 (1990).
Koch, M. C. et al. J. med. Genet. 28, 583–586 (1991).
Ptacek, L. J., Tyler, F., Trimmer, J. S., Agnew, W. S. & Leppert, M. Am. J. hum. Genet. 49, 378–382 (1991).
Trimmer, J. S. et al. Neuron 3, 33–49 (1989).
Yellen, G., Jurman, M. E., Abramson, T. & MacKinnon, R. Science 251, 939–941 (1991).
Yool, A. J. & Schwarz, T. L. Nature 349, 700–704 (1991).
Hartmann, H. A. et al. Science 251, 942–944 (1991).
Guy, H. R. & Conti, F. Trends Neurosci. 13, 201–206 (1990).
Hoshi, T., Zagotta, W. & Aldrich, R. Neuron 7, 547–556 (1991).
Stuhmer, W. et al. Nature 339, 597–603 (1989).
Moorman, J. R. et al. Science 250, 688–691 (1990).
Catterall, W. A. Science 242, 50–61 (1988).
Koch, M. C. et al. Hum. Genet. (in the press).
Ptacek, L. J. et al. Am. J. hum. Genet. 49, 378–382 (1991).
Miller, C. Science 252, 1092–1096 (1991).
Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual 2nd edn (Cold Spring Harbor Laboratory Press, New York, 1989).
Noda, M. et al. Nature 312, 121–127 (1984).
Noda, M. et al. Nature 320, 188–192 (1986).
Kayano, T., Noda, M., Flockerzi, V., Takahashi, H. & Numa, S. FEBS Lett. 228, 187–194 (1988).
Salkoff, L. et al. Science 237, 744–749 (1987).
Loughney, K., Kreber, R. & Ganetzky, B. Cell 58, 1143–1154 (1989).
Kallen, R. G. et al. Neuron 4, 233–242 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/354387a0
- Springer Nature Limited
This article is cited by
-
Ion channelopathies to bridge molecular lesions, channel function, and clinical therapies
Pflügers Archiv - European Journal of Physiology (2020)
-
Physicochemical Evolution and Molecular Adaptation of the Cetacean Osmoregulation-related Gene UT-A2 and Implications for Functional Studies
Scientific Reports (2015)
-
Mutational Consequences of Aberrant Ion Channels in Neurological Disorders
The Journal of Membrane Biology (2014)
-
Molecular differential expression of voltage-gated sodium channel α and β subunit mRNAs in five different mammalian cell lines
Journal of Bioenergetics and Biomembranes (2011)
-
Sodium channelopathies of skeletal muscle result from gain or loss of function
Pflügers Archiv - European Journal of Physiology (2010)