SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia
Copyright policy )SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia
Significance Cardiovascular disease remains the leading cause of mortality in the United States, and cardiac arrhythmia underlies the majority of these deaths. Here, we report a new mechanism for congenital human cardiac arrhythmia due to defects in the regulation of the primary cardiac Na v channel, Na v 1.5 ( SCN5A ), by a family of signaling molecules termed fibroblast growth factor homologous factors (FHFs). Individuals harboring SCN5A variants that affect Na v 1.5/FHF interactions display atrial and ventricular phenotypes, syncope, and sudden cardiac death. The human variant results in aberrant Na v 1.5 inactivation, causing prolonged action potential duration and afterdepolarizations in murine myocytes, thereby providing a rationale for the human arrhythmia.
- The Ohio State University United States
- Duke University Hospital United States
- Duke Medical Center United States
- Duke University United States
- University of California, San Francisco United States
Male, Patch-Clamp Techniques, Cells, Immunoblotting, Mutation, Missense, Action Potentials, Mice, Transgenic, Arrhythmias, Cardiovascular, Inbred C57BL, Transgenic, NAV1.5 Voltage-Gated Sodium Channel, Mice, channelopathy, Genetics, 2.1 Biological and endogenous factors, Animals, Humans, atrial fibrillation, Genetic Predisposition to Disease, Myocytes, Cardiac, Aetiology, Cells, Cultured, Nav1.5, Family Health, Myocytes, Cultured, Arrhythmias, Cardiac, Pedigree, Fibroblast Growth Factors, Mice, Inbred C57BL, Heart Disease, HEK293 Cells, Mutation, ion channel, Channelopathies, Female, Missense, Cardiac, Protein Binding, FHF
Male, Patch-Clamp Techniques, Cells, Immunoblotting, Mutation, Missense, Action Potentials, Mice, Transgenic, Arrhythmias, Cardiovascular, Inbred C57BL, Transgenic, NAV1.5 Voltage-Gated Sodium Channel, Mice, channelopathy, Genetics, 2.1 Biological and endogenous factors, Animals, Humans, atrial fibrillation, Genetic Predisposition to Disease, Myocytes, Cardiac, Aetiology, Cells, Cultured, Nav1.5, Family Health, Myocytes, Cultured, Arrhythmias, Cardiac, Pedigree, Fibroblast Growth Factors, Mice, Inbred C57BL, Heart Disease, HEK293 Cells, Mutation, ion channel, Channelopathies, Female, Missense, Cardiac, Protein Binding, FHF
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