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A calcium channel mutant mouse model of hypokalemic periodic paralysis
Fenfen Wu, … , Martin F. Schneider, Stephen C. Cannon
Fenfen Wu, … , Martin F. Schneider, Stephen C. Cannon
Published November 26, 2012
Citation Information: J Clin Invest. 2012;122(12):4580-4591. https://doi.org/10.1172/JCI66091.
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Research Article Article has an altmetric score of 17

A calcium channel mutant mouse model of hypokalemic periodic paralysis

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Abstract

Hypokalemic periodic paralysis (HypoPP) is a familial skeletal muscle disorder that presents with recurrent episodes of severe weakness lasting hours to days associated with reduced serum potassium (K+). HypoPP is genetically heterogeneous, with missense mutations of a calcium channel (CaV1.1) or a sodium channel (NaV1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between CaV1.1 mutations and the ictal loss of muscle excitability during an attack of weakness in HypoPP is unknown. To address this question, we developed a mouse model for HypoPP with a targeted CaV1.1 R528H mutation. The Cav1.1 R528H mice had a HypoPP phenotype for which low K+ challenge produced a paradoxical depolarization of the resting potential, loss of muscle excitability, and weakness. A vacuolar myopathy with dilated transverse tubules and disruption of the triad junctions impaired Ca2+ release and likely contributed to the mild permanent weakness. Fibers from the CaV1.1 R528H mouse had a small anomalous inward current at the resting potential, similar to our observations in the NaV1.4 R669H HypoPP mouse model. This “gating pore current” may be a common mechanism for paradoxical depolarization and susceptibility to HypoPP arising from missense mutations in the S4 voltage sensor of either calcium or sodium channels.

Authors

Fenfen Wu, Wentao Mi, Erick O. Hernández-Ochoa, Dennis K. Burns, Yu Fu, Hillery F. Gray, Arie F. Struyk, Martin F. Schneider, Stephen C. Cannon

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Figure 1

Construction and genetic analysis of the CaV1.1 R528H mouse.

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Construction and genetic analysis of the CaV1.1 R528H mouse.
 
(A) A sch...
(A) A schematic diagram of the α1S subunit for the CaV1.1 calcium channel shows the locations for all known HypoPP mutations. All are missense substitutions, with 6 of 7 being at arginines in voltage-sensor domains (red triangles) and 1 in an adjacent transmembrane segment (orange triangle). The R528H mutation is in the outermost arginine of the S4 segment in domain II. (B) The targeting construct for homologous recombination in mouse CACN1S contained the R528H mutation and a silent EcoRV site. Primers A and B were used for genotyping and are complementary to intronic sequence flanking exon 11. (C) PCR amplification from genomic DNA shows a 500-bp WT amplimer and a 580-bp mutant amplimer with a Cre-deleted NeoR gene and retention of a short intronic LoxP site. Correct insertion of the R528H mutation was confirmed by sequencing. EcoRV digest cut the entire 580-bp product from R528Hm/m mice but did not cut the 500-bp amplimer from WT or R528H+/m mice. (D) Expression of WT (+/+) and R528H RNA was determined with RT-PCR using allele-specific forward primers and a reverse primer from the next exon. The agarose gel shows allele specificity with a 128-bp product with only the R primer in WT and only the H primer in R528Hm/m.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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