| http://purl.uniprot.org/citations/26392562 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/26392562 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/26392562 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.org/dc/terms/identifier | "doi:10.1073/pnas.1516430112"xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.org/dc/terms/identifier | "doi:10.1073/pnas.1516430112"xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Wang C."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Wang C."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Yan H."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Yan H."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Pitt G.S."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Pitt G.S."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Salazar C."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Salazar C."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Weiss R."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Weiss R."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Sturm A.C."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Sturm A.C."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Kline C.F."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Kline C.F."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Mohler P.J."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Mohler P.J."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Hund T.J."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Hund T.J."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Murphy N."xsd:string |
| http://purl.uniprot.org/citations/26392562 | http://purl.uniprot.org/core/author | "Murphy N."xsd:string |