Characterization of a new sodium channel mutation at arginine 1448 associated with moderate paramyotonia congenita in humans

Saïd Bendahhou, Theodore Cummins, Hubert Kwiecinski, Stephen G. Waxman, Louis J. Ptácek

Research output: Contribution to journalArticle

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Abstract

1. Paramyotonia congenita is a temperature-sensitive skeletal muscle disorder caused by missense mutations that occur in the adult skeletal muscle voltage-gated sodium channel. We report here the identification of a new genetic mutation in a family with the paramyotonia congenita phenotype. 2. Single-strand conformation polymorphism analysis and DNA sequencing showed that the defect was linked to a single nucleotide substitution causing an amino acid change from an arginine to a serine at position 1448 in the human sodium channel α-subunit. 3. Expression of the altered protein in human embryonic kidney (HEK) 293 cells revealed several defects in channel function: (i) the rate of fast inactivation was slower in the mutant channel compared with wild-type, (ii) steady-state fast inactivation was shifted towards hyperpolarizing potentials, (iii) the R1448S channels deactivated much more slowly, and (iv) the mutant channels recovered from the fast inactivated state more rapidly. 4. By contrast, the activation curve, steady-state slow inactivation and the rate of onset and recovery from slow inactivation were not altered by the R1448S mutation. 5. These data show that the defects observed in the sodium channel function could well explain the onset of the paramyotonia congenita in this family and emphasize the role of segment S4 of domain IV in sodium channel inactivation.

Original languageEnglish (US)
Pages (from-to)337-344
Number of pages8
JournalJournal of Physiology
Volume518
Issue number2
DOIs
StatePublished - Jul 15 1999
Externally publishedYes

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Myotonic Disorders
Sodium Channels
Arginine
Mutation
Skeletal Muscle
Voltage-Gated Sodium Channels
Muscular Diseases
Missense Mutation
Amino Acid Substitution
DNA Sequence Analysis
Serine
Nucleotides
Phenotype
Kidney
Temperature
Proteins

ASJC Scopus subject areas

  • Physiology

Cite this

Characterization of a new sodium channel mutation at arginine 1448 associated with moderate paramyotonia congenita in humans. / Bendahhou, Saïd; Cummins, Theodore; Kwiecinski, Hubert; Waxman, Stephen G.; Ptácek, Louis J.

In: Journal of Physiology, Vol. 518, No. 2, 15.07.1999, p. 337-344.

Research output: Contribution to journalArticle

Bendahhou, Saïd ; Cummins, Theodore ; Kwiecinski, Hubert ; Waxman, Stephen G. ; Ptácek, Louis J. / Characterization of a new sodium channel mutation at arginine 1448 associated with moderate paramyotonia congenita in humans. In: Journal of Physiology. 1999 ; Vol. 518, No. 2. pp. 337-344.
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