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A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis
Fenfen Wu, … , Arie F. Struyk, Stephen C. Cannon
Fenfen Wu, … , Arie F. Struyk, Stephen C. Cannon
Published September 1, 2011
Citation Information: J Clin Invest. 2011;121(10):4082-4094. https://doi.org/10.1172/JCI57398.
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Research Article Muscle biology

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

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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

Fenfen Wu, Wentao Mi, Dennis K. Burns, Yu Fu, Hillery F. Gray, Arie F. Struyk, Stephen C. Cannon

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Figure 4

In vivo reduction of muscle excitability and force from glucose plus insulin challenge.

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In vivo reduction of muscle excitability and force from glucose plus ins...
(A) CMAP (black) and force (blue) at the Achilles tendon were recorded simultaneously in response to a single 0.1-ms shock (red) applied to the sciatic nerve. Sample tracings are from a single trial (nonaveraged) recorded from a R669H+/m mouse. (B) Baseline CMAP amplitude and force, recorded before glucose plus insulin infusion. Relative change in CMAP amplitude (C) and twitch force (D) in response to glucose and insulin infusion. Amplitudes were normalized to the average of 5 trials before the start of the infusion (vertical dashed lines). (E) Individual CMAP responses are superimposed for the first 20 responses, measured at 1-minute intervals, after glucose plus insulin infusion for WT and R669Hm/m animals. (F) The duration of the CMAP (peak to peak) was prolonged for R669H mutants and increased during glucose plus insulin infusion. (B–D) Responses are averaged (n = 16 [WT]; 8 [R669H+/m]; 7 [R669Hm/m]).

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