title: A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis.
abstract: 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.
authors: Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, Texas 75390-8813, USA.
authors: Fenfen
authors: F
authors: Wu
authors: Wentao
authors: W
authors: Mi
authors: Dennis K
authors: DK
authors: Burns
authors: Yu
authors: Y
authors: Fu
authors: Hillery F
authors: HF
authors: Gray
authors: Arie F
authors: AF
authors: Struyk
authors: Stephen C
authors: SC
authors: Cannon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D005947:Glucose / Q000494:pharmacology; D006720:Homozygote; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000235:genetics* / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D062553:NAV1.4 Voltage-Gated Sodium Channel; D010042:Ouabain / Q000494:pharmacology; D010641:Phenotype; D011188:Potassium / Q000494:pharmacology; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
chemical_list: D007328:Insulin; D050505:Mutant Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; C491391:Scn4a protein, mouse; D015222:Sodium Channels; D010042:Ouabain; D005947:Glucose; D011188:Potassium