Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current

Karin Jurkat-Rott, Nenad Mitrovic, Chao Hang, Alexei Kouzmekine, Paul Iaizzo, Jürgen Herzog, Holger Lerche, Sophie Nicole, Jose Vale-Santos, Dominique Chauveau, Bertrand Fontaine, Frank Lehmann-Horn

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The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor. In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672→His and →Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel α subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers from a patient heterozygous for Arg-672→Gly displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wild-type channel population only. Heterologous expression of the two sodium channel mutations revealed a 10-mV left shift of the steady-state fast inactivation curve enhancing inactivation and a sodium current density that was reduced even at potentials at which inactivation was removed. Decreased current and small action potentials suggested a low channel protein density. The alterations are decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels particularly at sustained membrane depolarization. The results prove that SCN4A, the gene encoding the sodium channel α subunit of skeletal muscle is responsible for HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease caused by enhanced channel inactivation and current reduction showing no myotonia.

Original languageEnglish (US)
Pages (from-to)9549-9554
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Aug 15 2000


  • Channelopathy
  • Functional expression
  • Molecular genetics
  • Muscle disease


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