In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 40 ( 2015-10-06), p. 12528-12533
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1516430112
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2015
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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