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Journal article
Defective Fast Inactivation Recovery of Na(v)1.4 in Congenital Myasthenic Syndrome
Annals of neurology, v 77(5), pp 840-850
01 May 2015
PMID: 25707578
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Abstract
ObjectiveTo describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology.
MethodsWe used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Na(v)1.4.
ResultsClinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Na(v)1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel's voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics.
InterpretationWe conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient's muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel's involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function. Ann Neurol 2015;77:840-850
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Details
- Title
- Defective Fast Inactivation Recovery of Na(v)1.4 in Congenital Myasthenic Syndrome
- Creators
- W. David Arnold - The Ohio State University Wexner Medical CenterDaniel H. Feldman - University of California, DavisSandra Ramirez - University of California, DavisLiuyuan He - University of California, DavisDarine Kassar - The Ohio State University Wexner Medical CenterAdam Quick - The Ohio State University Wexner Medical CenterTara L. Klassen - University of British ColumbiaMarian Lara - University of California, DavisJoanna Nguyen - University of California, DavisJohn T. Kissel - The Ohio State University Wexner Medical CenterChristoph Lossin - University of California, DavisRicardo A. Maselli - University of California, DavisLin He - Chemistry
- Publication Details
- Annals of neurology, v 77(5), pp 840-850
- Publisher
- Wiley
- Number of pages
- 11
- Grant note
- 5K12HD001097-17 / NIH National Institute of Child Health and Human Development; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) K12HD001097 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000353235400012
- Scopus ID
- 2-s2.0-84928138708
- Other Identifier
- 991019173442204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology
- Neurosciences