ArticleProceedings of the National Academy of Sciences of the United States of America2015
SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 64 citations in OpenAlex.
- FGF23 promotes atrial fibrillation susceptibility through ETV1-dependent sodium channel regulation and calcium handling abnormalities.Experimental physiology · 2026Article
- Targeting Arrhythmogenic Late Sodium Current by FHF1Circulation research · 2026Article
- FGF13 Regulates VGSC-Independent Cardiomyocyte Impulse Propagation via Cx43 Trafficking.Circulation research · 2025Article
- Article
- The NaV1.5 auxiliary subunit FGF13 modulates channels by regulating membrane cholesterol independent of channel binding.The Journal of clinical investigation · 2025Article
- Effects of open-channel blocking peptides in NaBiophysical journal · 2025Article
- The Extent of Edgetic Perturbations in the Human Interactome Caused by Population-Specific Mutations.Biomolecules · 2023Article
- Determinants of iFGF13-mediated regulation of myocardial voltage-gated sodium (NaV) channels in mouse.The Journal of general physiology · 2023Article
- Microtubule plus-end tracking proteins: novel modulators of cardiac sodium channels and arrhythmogenesis.Cardiovascular research · 2023Article
- Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors.The Journal of general physiology · 2023Article
- Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes.Pflugers Archiv : European journal of physiology · 2023Article
- BIOLOGICAL ANTIARRHYTHMICS-SODIUM CHANNEL INTERACTING PROTEINS.Transactions of the American Clinical and Climatological Association · 2023Article
- FGF12 is a novel component of the nucleolar NOLC1/TCOF1 ribosome biogenesis complex.Cell communication and signaling : CCS · 2022Article
- Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.Nature cardiovascular research · 2022Article
- Ion Channel and Ubiquitin Differential Expression during Erythromycin-Induced Anhidrosis in Foals.Animals : an open access journal from MDPI · 2021Article
- Ca2+-dependent modulation of voltage-gated myocyte sodium channels.Biochemical Society transactions · 2021Review
- Nav1.3 and FGF14 are primary determinants of the TTX-sensitive sodium current in mouse adrenal chromaffin cells.The Journal of general physiology · 2021Article
- Differential Modulation of the Voltage-Gated NaFrontiers in molecular biosciences · 2021Article
- Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart.Circulation research · 2020Article
- Characterization of an N-terminal NaBMC medical genetics · 2020Article
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.
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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.