Hypokalemic periodic paralysis (HypoPP) is a dominantly inherited disorder of skeletal muscle in which recurrent attacks of weakness are caused by intermittent failure of fiber electrical excitability. Episodes occur in association with hypokalemia (K+ < 3 mM) and may be triggered by carbohydrate ingestion, exercise, or stress. The molecular defect in HypoPP is heterogeneous, with 60% of families having missense mutations in CACNA1S encoding the L-type Ca channel CaV1.1, another 20% have missense mutations in SCN4A encoding the voltage-gated Na channel NaV1.4, and the remainder undetermined. Despite this scientific advance, the pathogenic basis for the transient attacks of fiber depolarization with loss of excitability is not fully established. Curiously, all 8 mutationsin NaV1.4 and 6 of 7 in CaV1.1 occur at arginine residues in S4 voltage-sensor domains. Thus far, all 6 NaV1.4-HypoPP mutations studied in the cut-open oocyte have revealed a small anomalous cation current activated at hyperpolarized potentials, via conduction through a gating pore between the mutated S4 segment and the channel protein. We recently reported a gating pore current in muscle fibers from NaV1.4-R669H mice. This gating pore conductance is hypothesized to be the source of the inward current that triggers the paradoxical depolarization of HypoPP fibers in low K+. A major unanswered question is whether the homologous R/X mutations in CaV1.1 associated with HypoPP also produce a gating pore current, thereby providing supportive evidence for a common pathomechanism for HypoPP arising from mutations in NaV1.1 or CaV1.1. The overall goal of this project is to gain a greater understanding for the pathologic basis of HypoPP resulting from CaV1.1 mutations. We have used a gene-targeting approach to generate an R528H knockin mutation of CaV1.1 as a model for HypoPP.
The Aims of this project are: (1) to extend the phenotypic characterization of the CaV1.1-R528H mouse for features of hypokalemic periodic paralysis, (2) to test the hypothesis that the CaV1.1-R528H channel conducts an anomalous gating pore current (3) to characterize the integrity of Ca2+- release in CaV1.1-R528H muscle fibers, (4) to explore potential disease-modifying agents in the mouse model of CaV1.1-HypoPP. This work will extend our understanding of the pathogenesis for attacks of weakness in HypoPP and will provide a model system to test the efficacy of therapeutic strategies, both as a means to reduce or ameliorate the burden of disease and to provide confirmatory experimental support for the proposed mechanism of disease.

Public Health Relevance

Familial periodic paralysis is a rare disorder of skeletal muscle in which intermittent failure of muscle excitability causes attacks of severe weakness or paralysis lasting for hours to days. The molecular defect has been known for more than a decade to be mutations of either calcium channels or sodium channels, but the mechanisms by which these channel defects cause susceptibility to attacks of weakness are poorly understood and consequently rational therapeutic strategies to modify disease course are lacking. We have developed the only genetically-engineered mouse model of periodic paralysis based on a calcium channel mutation and will use this unique tool to define further the mechanism underlying attacks of paralysis and test potential interventions to modify disease burden.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Wu, Fenfen; Quinonez, Marbella; DiFranco, Marino et al. (2018) Stac3 enhances expression of human CaV1.1 in Xenopus oocytes and reveals gating pore currents in HypoPP mutant channels. J Gen Physiol :
Cannon, Stephen C (2017) An atypical CaV1.1 mutation reveals a common mechanism for hypokalemic periodic paralysis. J Gen Physiol 149:1061-1064
Sansone, Valeria A; Burge, James; McDermott, Michael P et al. (2016) Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis. Neurology 86:1408-1416
Nelson, Benjamin R; Makarewich, Catherine A; Anderson, Douglas M et al. (2016) A peptide encoded by a transcript annotated as long noncoding RNA enhances SERCA activity in muscle. Science 351:271-5
Cannon, Stephen C (2015) Channelopathies of skeletal muscle excitability. Compr Physiol 5:761-90
Nelson, Benjamin R; Wu, Fenfen; Liu, Yun et al. (2013) Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility. Proc Natl Acad Sci U S A 110:11881-6
Wu, Fenfen; Mi, Wentao; Cannon, Stephen C (2013) Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis. Brain 136:3766-74
Wu, Fenfen; Mi, Wentao; Hernández-Ochoa, Erick O et al. (2012) A calcium channel mutant mouse model of hypokalemic periodic paralysis. J Clin Invest 122:4580-91