期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 40, 页码 12528-12533出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1516430112
关键词
ion channel; channelopathy; atrial fibrillation; Nav1.5; FHF
资金
- NIH [HL114893, HL084583, HL083422, HL114383, HL071165]
- James S. McDonnell Foundation
- American Heart Association
Na-v channels are essential for metazoan membrane depolarization, and Na-v channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Na-v channelopathies are primarily caused by variants that directly affect Na-v channel permeability or gating. However, a new class of human Na-v 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 Na-v channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Na-v channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Na-v channel Na(v)1.5) 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 Na(v)1.5 for FHFs. Consistent with these data, Na(v)1.5 p. H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Na(v)1.5 p. H1849R as a gain-of-function for I-Na by altering steady-state inactivation and slowing the rate of Na(v)1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Na(v)1.5 p. H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Na-v channelopathy based on altered Na(v)1.5 association with FHF proteins.
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