| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Adelman, Sara Wang, Chaojian Weiss, Raul Salazar, Christina Higgins, Robert S. D. Hund, Thomas J. Fedorov, Vadim V. Johnson, Benjamin L. Sturm, Amy C. Musa, Hassan Kline, Crystal F. Kilic, Ahmet Mohler, Peter J. Csepe, Thomas A. Yan, Haidun Janssen, Paul M. L. Pitt, Geoffrey S. Murphy, Nathaniel |
| Description |
Author Affiliation: Musa H ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Kline CF ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Sturm AC ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Murphy N ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Adelman S ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Wang C ( Department of Medicine and Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27709); Yan H ( Department of Medicine and Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27709); Johnson BL ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Csepe TA ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Kilic A ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Higgins RS ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Janssen PM ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Fedorov VV ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Weiss R ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Salazar C ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Hund TJ ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); Pitt GS ( Department of Medicine and Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27709); Mohler PJ ( Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210); |
| 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. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
40 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-10-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Arrhythmias, Cardiac Genetics Fibroblast Growth Factors Metabolism Mutation, Missense NAV1.5 Voltage-Gated Sodium Channel Action Potentials Physiology Animals Physiopathology Cells, Cultured Channelopathies Family Health Genetic Predisposition To Disease HEK293 Cells Immunoblotting Mice, Inbred C57BL Mice, Transgenic Myocytes, Cardiac Patch-Clamp Techniques Pedigree Protein Binding Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
