A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation

Saïd Bendahhou, Theodore Cummins, Angelika F. Hahn, Sylvie Langlois, Stephen G. Waxman, Louis J. Ptácek

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Hyperkalemic periodic paralysis (HyperKPP) is an autosomal dominant skeletal muscle disorder caused by single mutations in the SCN4A gene, encoding the human skeletal muscle voltage-gated Na+ channel. We have now identified one allele with two novel mutations occurring simultaneously in the SCN4A gene. These mutations are found in two distinct families that had symptoms of periodic paralysis and malignant hyperthermia susceptibility. The two nucleotide transitions predict phenylalanine 1490→leucine and methionine 1493→isoleucine changes located in the transmembrane segment S5 in the fourth repeat of the α-subunit Na+ channel. Surprisingly, this mutation did not affect fast inactivation parameters. The only defect produced by the double mutant (F1490L-M1493I, expressed in human embryonic kidney 293 cells) is an enhancement of slow inactivation, a unique behavior not seen in the 24 other disease-causing mutations. The behavior observed in these mutant channels demonstrates that manifestation of HyperKPP does not necessarily require disruption of slow inactivation. Our findings may also shed light on the molecular determinants and mechanism of Na+ channel slow inactivation and help clarify the relationship between Na+ channel defects and the long-term paralytic attacks experienced by patients with HyperKPP.

Original languageEnglish (US)
Pages (from-to)431-438
Number of pages8
JournalJournal of Clinical Investigation
Volume106
Issue number3
StatePublished - 2000
Externally publishedYes

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Sodium Channels
Hyperkalemic Periodic Paralysis
Paralysis
Mutation
Skeletal Muscle
Malignant Hyperthermia
Muscular Diseases
Phenylalanine
Methionine
Genes
Nucleotides
Alleles
Kidney

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation. / Bendahhou, Saïd; Cummins, Theodore; Hahn, Angelika F.; Langlois, Sylvie; Waxman, Stephen G.; Ptácek, Louis J.

In: Journal of Clinical Investigation, Vol. 106, No. 3, 2000, p. 431-438.

Research output: Contribution to journalArticle

Bendahhou, S, Cummins, T, Hahn, AF, Langlois, S, Waxman, SG & Ptácek, LJ 2000, 'A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation', Journal of Clinical Investigation, vol. 106, no. 3, pp. 431-438.
Bendahhou, Saïd ; Cummins, Theodore ; Hahn, Angelika F. ; Langlois, Sylvie ; Waxman, Stephen G. ; Ptácek, Louis J. / A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation. In: Journal of Clinical Investigation. 2000 ; Vol. 106, No. 3. pp. 431-438.
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