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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 9

Vacuolar myopathy in gastrocnemius muscle from R528H mice.

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Vacuolar myopathy in gastrocnemius muscle from R528H mice.
(A) Transvers...
(A) Transverse 10-μm cryostat sections stained with H&E and NADH-TR demonstrated small, optically clear central vacuoles (arrows) in R528Hm/m fibers. Longitudinal 1.5-μm sections of resin-embedded fibers stained with toluidine blue show the linear extent of the vacuoles. Vacuolar changes were not detected by light microscopy in WT or R528H+/m fibers. Scale bars: 100 μm. (B) Ultrastructural studies from gastrocnemius muscle showed large, well-demarcated vacuoles with disruption of the triad junction in R528Hm/m fibers. Some vacuoles were continuous, with membrane-lined protuberances oriented transversely to the fiber axis (arrow, bottom right), suggesting that the vacuoles were dilated transverse tubules. Other sections showed large vacuoles at the normal position of the junctional SR, suggesting dilation of the sarcoplasmic reticulum as well. A lower-magnification EM image demonstrates that the vacuolar changes were extensive, with a substantial portion of sarcomeres being affected in R528Hm/m muscle (bottom left). Rare, mildly dilated cisternae of the sarcoplasmic reticulum were observed in heterozygous R528H+/m muscle, although no large vacuoles were observed of the type present in homozygous R528H fibers. No ultrastructural abnormalities were present in the WT muscle. Scale bars: 2 μm.

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

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