ArticleProceedings of the National Academy of Sciences of the United States of America2000
Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers, 2 of them syntheses that pooled it.
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Who cites it
97 citing papers in PubMed, 2 syntheses or guidelines pooled it, 265 citations in OpenAlex.
- Targeted Therapies for Skeletal Muscle Ion Channelopathies: Systematic Review and Steps Towards Precision Medicine.Journal of neuromuscular diseases · 2021Pooled it
- Diagnostics and therapy of muscle channelopathies--Guidelines of the Ulm Muscle Centre.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2008Guideline
- Trial
- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
- Novel SCN4A Variants Associated With Myalgic Myotonic Disorder or Paramyotonia.European journal of neurology · 2025Article
- Voltage-gated sodium channels in excitable cells as drug targets.Nature reviews. Drug discovery · 2025Review
- Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium channels.iScience · 2024Article
- Diagnosis, management and outcomes of primary hypokalemic periodic paralysis during pregnancy.Obstetric medicine · 2024Article
- Genetic analysis of 37 cases with primary periodic paralysis in Chinese patients.Orphanet journal of rare diseases · 2024Article
- Article
- Periodic paralysis.Handbook of clinical neurology · 2024Review
- Functional effects of drugs and toxins interacting with NaFrontiers in pharmacology · 2024Review
- Hypokalemic periodic paralysis: a 3-year follow-up study.Journal of neurology · 2023Article
- Ion currents through the voltage sensor domain of distinct families of proteins.Journal of biological physics · 2023Review
- Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells.Disease models & mechanisms · 2023Article
- Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan.Frontiers in neurology · 2023Article
- The voltage-sensing domain of a hERG1 mutant is a cation-selective channel.Biophysical journal · 2022Article
- MicroRNA is a potential target for therapies to improve the physiological function of skeletal muscle after trauma.Neural regeneration research · 2022Article
- Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes.Neurogenetics · 2022Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
37 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor. In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672-->His and -->Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel alpha subunit, known to be responsible for hereditary muscle diseases associated with myotonia. Excised skeletal muscle fibers from a patient heterozygous for Arg-672-->Gly displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wild-type channel population only. Heterologous expression of the two sodium channel mutations revealed a 10-mV left shift of the steady-state fast inactivation curve enhancing inactivation and a sodium current density that was reduced even at potentials at which inactivation was removed. Decreased current and small action potentials suggested a low channel protein density. The alterations are decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels particularly at sustained membrane depolarization. The results prove that SCN4A, the gene encoding the sodium channel alpha subunit of skeletal muscle is responsible for HypoPP-2 which does not differ clinically from DHPR-HypoPP. HypoPP-2 represents a disease caused by enhanced channel inactivation and current reduction showing no myotonia.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.