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A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.1) and a sodium channel (NaV1.4) have been identified in HypoPP families. Mutations of NaV1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the NaV1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the NaV1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K+ challenge, insensitivity to high-K+ challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na+/K+-ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant NaV1.4 channels.

Pubmed ID: 21881211


  • Wu F
  • Mi W
  • Burns DK
  • Fu Y
  • Gray HF
  • Struyk AF
  • Cannon SC


The Journal of clinical investigation

Publication Data

October 3, 2011

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR-42703
  • Agency: NIAMS NIH HHS, Id: R37 AR042703

Mesh Terms

  • Amino Acid Substitution
  • Animals
  • Disease Models, Animal
  • Female
  • Gene Knock-In Techniques
  • Glucose
  • Homozygote
  • Humans
  • Hypokalemic Periodic Paralysis
  • Insulin
  • Isometric Contraction
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mutagenesis, Site-Directed
  • Mutant Proteins
  • NAV1.4 Voltage-Gated Sodium Channel
  • Ouabain
  • Phenotype
  • Potassium
  • Sodium Channels