SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia

Hassan Musa, Crystal F. Kline, Amy C. Sturm, Nathaniel Murphy, Sara Adelman, Chaojian Wang, Haidun Yan, Benjamin L. Johnson, Thomas A. Csepe, Ahmet Kilic, Robert Higgins, Paul M L Janssen, Vadim V. Fedorov, Raul Weiss, Christina Salazar, Thomas J. Hund, Geoffrey S. Pitt, Peter J. Mohler, Louis J. Ptáček

Research output: Contribution to journalArticle

Abstract

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 &z.ast;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 after depolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.

Original languageEnglish (US)
Pages (from-to)12528-12533
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number40
DOIs
StatePublished - Oct 6 2015
Externally publishedYes

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Fibroblast Growth Factors
Cardiac Arrhythmias
Channelopathies
Intracellular Signaling Peptides and Proteins
Myotonia
Cytoskeletal Proteins
Irritable Bowel Syndrome
Sudden Cardiac Death
Ataxia
Heart Arrest
Cardiac Myocytes
Muscle Cells
Action Potentials
Permeability
Epilepsy
Cardiovascular Diseases
Phenotype
Neurons
Pain
Mutation

Keywords

  • Atrial fibrillation
  • Channelopathy
  • FHF
  • Ion channel
  • Nav1.5

ASJC Scopus subject areas

  • General

Cite this

SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia. / Musa, Hassan; Kline, Crystal F.; Sturm, Amy C.; Murphy, Nathaniel; Adelman, Sara; Wang, Chaojian; Yan, Haidun; Johnson, Benjamin L.; Csepe, Thomas A.; Kilic, Ahmet; Higgins, Robert; Janssen, Paul M L; Fedorov, Vadim V.; Weiss, Raul; Salazar, Christina; Hund, Thomas J.; Pitt, Geoffrey S.; Mohler, Peter J.; Ptáček, Louis J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 40, 06.10.2015, p. 12528-12533.

Research output: Contribution to journalArticle

Musa, H, Kline, CF, Sturm, AC, Murphy, N, Adelman, S, Wang, C, Yan, H, Johnson, BL, Csepe, TA, Kilic, A, Higgins, R, Janssen, PML, Fedorov, VV, Weiss, R, Salazar, C, Hund, TJ, Pitt, GS, Mohler, PJ & Ptáček, LJ 2015, 'SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 40, pp. 12528-12533. https://doi.org/10.1073/pnas.1516430112
Musa, Hassan ; Kline, Crystal F. ; Sturm, Amy C. ; Murphy, Nathaniel ; Adelman, Sara ; Wang, Chaojian ; Yan, Haidun ; Johnson, Benjamin L. ; Csepe, Thomas A. ; Kilic, Ahmet ; Higgins, Robert ; Janssen, Paul M L ; Fedorov, Vadim V. ; Weiss, Raul ; Salazar, Christina ; Hund, Thomas J. ; Pitt, Geoffrey S. ; Mohler, Peter J. ; Ptáček, Louis J. / SCN5A variant that blocks fibroblast growth factor homologous factor regulation causes human arrhythmia. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 40. pp. 12528-12533.
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AU - Musa, Hassan

AU - Kline, Crystal F.

AU - Sturm, Amy C.

AU - Murphy, Nathaniel

AU - Adelman, Sara

AU - Wang, Chaojian

AU - Yan, Haidun

AU - Johnson, Benjamin L.

AU - Csepe, Thomas A.

AU - Kilic, Ahmet

AU - Higgins, Robert

AU - Janssen, Paul M L

AU - Fedorov, Vadim V.

AU - Weiss, Raul

AU - Salazar, Christina

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N2 - 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 &z.ast;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 after depolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.

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