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Abstract
Objective: To electrophysiologically characterize the Nav1.4 mutant N440K found in a Korean family with a syndrome combining symptoms of paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia.
Methods: We characterized transiently expressed wild-type and mutant Nav1.4 using whole-cell voltage-clamp analysis.
Results: N440K produced a significant depolarizing shift in the voltage dependence of fast inactivation and increased persistent current and acceleration in fast inactivation recovery, which gave rise to a 2-fold elevation in the dynamic availability of the mutant channels. In addition, the mutant channels required substantially longer and stronger depolarization to enter the slow-inactivated state.
Conclusions: N440K causes a gain of function consistent with skeletal muscle hyperexcitability as observed in individuals with the mutation. How the same mutation results in distinct phenotypes in the 2 kindreds remains to be determined.
GLOSSARY
- ADM=
- abductor digiti minimi;
- CMAP=
- compound muscle action potential;
- LET=
- long exercise test;
- PEMP=
- postexercise myotonic potential;
- PMC=
- paramyotonia congenita;
- SET=
- short exercise test
Footnotes
Study funding: Supported in part by the University of California, Davis Innovative Development Award (to C.L.) and by grant A100402 from the Korea Health 21 R&D Project, Ministry of Health, Welfare & Family Affairs, Republic of Korea.
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Supplemental data at www.neurology.org
- Received December 22, 2011.
- Accepted April 19, 2012.
- Copyright © 2012 by AAN Enterprises, Inc.
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