SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia
| العنوان: | SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia |
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| المؤلفون: | Ahmet Kilic, Hassan Musa, Haidun Yan, Amy C. Sturm, Vadim V. Fedorov, Paul M.L. Janssen, Robert S.D. Higgins, Benjamin L. Johnson, Sara Adelman, Peter J. Mohler, Raul Weiss, Geoffrey S. Pitt, Christina Salazar, Thomas A. Csepe, Chaojian Wang, Nathaniel P. Murphy, Thomas J. Hund, Crystal F. Kline |
| المصدر: | Proceedings of the National Academy of Sciences. 112:12528-12533 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Patch-Clamp Techniques, Immunoblotting, Mutation, Missense, Action Potentials, Mice, Transgenic, Gating, Nav1.5, Fibroblast growth factor, NAV1.5 Voltage-Gated Sodium Channel, Afterdepolarization, Channelopathy, Internal medicine, Animals, Humans, Medicine, Myocyte, Genetic Predisposition to Disease, Myocytes, Cardiac, cardiovascular diseases, Cells, Cultured, Ion channel, Family Health, Multidisciplinary, biology, business.industry, Arrhythmias, Cardiac, Biological Sciences, medicine.disease, Myotonia, Pedigree, Cell biology, Fibroblast Growth Factors, Mice, Inbred C57BL, HEK293 Cells, Endocrinology, cardiovascular system, biology.protein, Channelopathies, Female, business, Protein Binding |
| الوصف: | 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. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d916ce7eee7e2b23a9f5440a4ae53c7 https://doi.org/10.1073/pnas.1516430112 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....1d916ce7eee7e2b23a9f5440a4ae53c7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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