Cell
Volume 77, Issue 6, 17 June 1994, Pages 863-868
Journal home page for Cell

Article
Dihydropyridine receptor mutations cause hypokalemic periodic paralysis

https://doi.org/10.1016/0092-8674(94)90135-XGet rights and content

Abstract

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant skeletal muscle disorder manifested by episodic weakness associated with low serum potassium. Genetic linkage analysis has localized the hypoKPP gene to chromosome 1q31–q32 near a dihydropyridine (DHP) receptor gene. This receptor functions as a voltage-gated calcium channel and is also critical for excitation-contraction coupling in a voltage-sensitive and calcium-independent manner. We have characterized patient-specific DHP receptor mutations in 11 probands of 33 independent hypoKPP kindreds that occur at one of two adjacent nucleotides within the same codon and predict substitution of a highly conserved arginine in the S4 segment of domain 4 with either histidine or glycine. In one kindred, the mutation arose de novo. Taken together, these data establish this DHP receptor as the hypoKPP gene. We are unaware of any other human diseases presently known to result from DHP receptor mutations.

References (38)

  • K. Wrogemann et al.

    Mitochondrial calcium overload: general mechanism for cell necrosis in muscle disease

    Lancet

    (1976)
  • R.L. Barchi

    Probing the molecular structure of the voltage-dependent sodium channel

    Annu. Rev. Neurosci.

    (1988)
  • K.G. Beam et al.

    A lethal mutation in mice eliminates the slow calcium current in skeletal muscle cells

    Nature

    (1986)
  • W.A. Catterall

    Structure and function of voltage-sensitive ion channels

    Science

    (1988)
  • J.Y. Cheung et al.

    Mechanisms of disease: calcium and ischemic injury

    N. Eng. J. Med.

    (1986)
  • G.C. Ebers et al.

    Paramyotonia congenita and hyperkalemic periodic paralysis are linked to the adult muscle sodium channel gene

    Ann. Neurol.

    (1991)
  • A.G. Engel

    Evolution and content of vacuoles in primary hypokalemic periodic paralysis

  • B. Fontaine et al.

    Hyperkalemic periodic paralysis and the adult muscle sodium channel gene

    Science

    (1990)
  • B. Fontaine et al.

    Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31–32 in three European families

    Nature Genet.

    (1994)
  • Cited by (393)

    • Management of metabolic disorders (including metabolic diseases) in ruminant and nonruminant animals

      2019, Animal Agriculture: Sustainability, Challenges and Innovations
    View all citing articles on Scopus
    View full text