title: SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia.
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.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Crystal F
authors.initials: CF
authors.lastname: Kline
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Internal Medicine, Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Amy C
authors.initials: AC
authors.lastname: Sturm
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Murphy
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Sara
authors.initials: S
authors.lastname: Adelman
authors.affiliation: Department of Medicine and Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27709;
authors.forename: Chaojian
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medicine and Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27709;
authors.forename: Haidun
authors.initials: H
authors.lastname: Yan
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Johnson
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Csepe
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Robert S D
authors.initials: RS
authors.lastname: Higgins
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Raul
authors.initials: R
authors.lastname: Weiss
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: Christina
authors.initials: C
authors.lastname: Salazar
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Biomedical Engineering College of Engineering, The Ohio State University, Columbus, OH 43210.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.affiliation: Department of Medicine and Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27709;
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH 43210; Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210; peter.mohler@osumc.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D053447:Channelopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005192:Family Health; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011485:Protein Binding
chemical_list: C486356:FGF12 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D005346:Fibroblast Growth Factors
keywords: FHF; Nav1.5; atrial fibrillation; channelopathy; ion channel