ArticleAnnals of neurology2015
Defective fast inactivation recovery of Nav 1.4 in congenital myasthenic syndrome.
Article in Annals of neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
42 citing papers in PubMed, 2 syntheses or guidelines pooled it, 65 citations in OpenAlex.
- Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine.Journal of neuromuscular diseases · 2021Pooled it
- Congenital myasthenic syndromes.Orphanet journal of rare diseases · 2019Pooled it
- Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition.The Journal of clinical investigation · 2026Article
- The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Review
- Molecular genetics of skeletal muscle channelopathies.Journal of human genetics · 2025Review
- Hydrops fetalis due to loss of function of hNav1.4 channel via compound heterozygous variants.Journal of human genetics · 2025Article
- Novel compound heterozygous mutations inHeliyon · 2024Article
- A retrospective study of accuracy and usefulness of electrophysiological exercise tests.Journal of neurology · 2024Article
- Article
- Periodic paralysis.Handbook of clinical neurology · 2024Review
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- Clinicopathological-genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre.Journal of cellular and molecular medicine · 2022Article
- Case report: NovelFrontiers in pediatrics · 2022Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
- New Challenges Resulting From the Loss of Function of NaFrontiers in pharmacology · 2021Review
- Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions.Frontiers in neurology · 2021Review
- Guidelines on clinical presentation and management of nondystrophic myotonias.Muscle & nerve · 2020Review
- Homozygous C-terminal loss-of-function NaJournal of neurology, neurosurgery, and psychiatry · 2020Article
- Central Role of Subthreshold Currents in Myotonia.Annals of neurology · 2020Review
- Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L769V Mutation inFrontiers in neurology · 2020Article
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
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 Nav 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 Nav 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.
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Registered trials
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