FGF12 is a candidate Brugada syndrome locus

Jessica A. Hennessey, Cherisse A. Marcou, Chuan Wang, Eric Q. Wei, Chaojian Wang, David J. Tester, Margherita Torchio, Federica Dagradi, Lia Crotti, Peter J. Schwartz, Michael John Ackerman, Geoffrey S. Pitt

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Background Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na + and Ca2+ channel currents, we hypothesized that FHFs are candidate BrS loci. Objective The goal of this study was to test whether FGF12 is a candidate BrS locus. Methods We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential. Results We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na+ channel current density and availability without affecting Ca2+ channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na+ channel function. Conclusions These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na+ and Ca2+ channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.

Original languageEnglish (US)
Pages (from-to)1886-1894
Number of pages9
JournalHeart Rhythm
Volume10
Issue number12
DOIs
StatePublished - Dec 2013

Fingerprint

Brugada Syndrome
Mutation
Cardiac Myocytes
Action Potentials
Fibroblast Growth Factors
Missense Mutation
Genotype
Phenotype
Polymerase Chain Reaction

Keywords

  • Brugada syndrome
  • Ca channels
  • Electrophysiology
  • Na channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Hennessey, J. A., Marcou, C. A., Wang, C., Wei, E. Q., Wang, C., Tester, D. J., ... Pitt, G. S. (2013). FGF12 is a candidate Brugada syndrome locus. Heart Rhythm, 10(12), 1886-1894. https://doi.org/10.1016/j.hrthm.2013.09.064

FGF12 is a candidate Brugada syndrome locus. / Hennessey, Jessica A.; Marcou, Cherisse A.; Wang, Chuan; Wei, Eric Q.; Wang, Chaojian; Tester, David J.; Torchio, Margherita; Dagradi, Federica; Crotti, Lia; Schwartz, Peter J.; Ackerman, Michael John; Pitt, Geoffrey S.

In: Heart Rhythm, Vol. 10, No. 12, 12.2013, p. 1886-1894.

Research output: Contribution to journalArticle

Hennessey, JA, Marcou, CA, Wang, C, Wei, EQ, Wang, C, Tester, DJ, Torchio, M, Dagradi, F, Crotti, L, Schwartz, PJ, Ackerman, MJ & Pitt, GS 2013, 'FGF12 is a candidate Brugada syndrome locus', Heart Rhythm, vol. 10, no. 12, pp. 1886-1894. https://doi.org/10.1016/j.hrthm.2013.09.064
Hennessey JA, Marcou CA, Wang C, Wei EQ, Wang C, Tester DJ et al. FGF12 is a candidate Brugada syndrome locus. Heart Rhythm. 2013 Dec;10(12):1886-1894. https://doi.org/10.1016/j.hrthm.2013.09.064
Hennessey, Jessica A. ; Marcou, Cherisse A. ; Wang, Chuan ; Wei, Eric Q. ; Wang, Chaojian ; Tester, David J. ; Torchio, Margherita ; Dagradi, Federica ; Crotti, Lia ; Schwartz, Peter J. ; Ackerman, Michael John ; Pitt, Geoffrey S. / FGF12 is a candidate Brugada syndrome locus. In: Heart Rhythm. 2013 ; Vol. 10, No. 12. pp. 1886-1894.
@article{2ea19a76089741458d169076e1e98081,
title = "FGF12 is a candidate Brugada syndrome locus",
abstract = "Background Less than 30{\%} of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na + and Ca2+ channel currents, we hypothesized that FHFs are candidate BrS loci. Objective The goal of this study was to test whether FGF12 is a candidate BrS locus. Methods We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential. Results We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na+ channel current density and availability without affecting Ca2+ channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na+ channel function. Conclusions These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na+ and Ca2+ channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.",
keywords = "Brugada syndrome, Ca channels, Electrophysiology, Na channels",
author = "Hennessey, {Jessica A.} and Marcou, {Cherisse A.} and Chuan Wang and Wei, {Eric Q.} and Chaojian Wang and Tester, {David J.} and Margherita Torchio and Federica Dagradi and Lia Crotti and Schwartz, {Peter J.} and Ackerman, {Michael John} and Pitt, {Geoffrey S.}",
year = "2013",
month = "12",
doi = "10.1016/j.hrthm.2013.09.064",
language = "English (US)",
volume = "10",
pages = "1886--1894",
journal = "Heart Rhythm",
issn = "1547-5271",
publisher = "Elsevier",
number = "12",

}

TY - JOUR

T1 - FGF12 is a candidate Brugada syndrome locus

AU - Hennessey, Jessica A.

AU - Marcou, Cherisse A.

AU - Wang, Chuan

AU - Wei, Eric Q.

AU - Wang, Chaojian

AU - Tester, David J.

AU - Torchio, Margherita

AU - Dagradi, Federica

AU - Crotti, Lia

AU - Schwartz, Peter J.

AU - Ackerman, Michael John

AU - Pitt, Geoffrey S.

PY - 2013/12

Y1 - 2013/12

N2 - Background Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na + and Ca2+ channel currents, we hypothesized that FHFs are candidate BrS loci. Objective The goal of this study was to test whether FGF12 is a candidate BrS locus. Methods We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential. Results We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na+ channel current density and availability without affecting Ca2+ channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na+ channel function. Conclusions These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na+ and Ca2+ channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.

AB - Background Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na + and Ca2+ channel currents, we hypothesized that FHFs are candidate BrS loci. Objective The goal of this study was to test whether FGF12 is a candidate BrS locus. Methods We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential. Results We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na+ channel current density and availability without affecting Ca2+ channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na+ channel function. Conclusions These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na+ and Ca2+ channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.

KW - Brugada syndrome

KW - Ca channels

KW - Electrophysiology

KW - Na channels

UR - http://www.scopus.com/inward/record.url?scp=84889795225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84889795225&partnerID=8YFLogxK

U2 - 10.1016/j.hrthm.2013.09.064

DO - 10.1016/j.hrthm.2013.09.064

M3 - Article

C2 - 24096171

AN - SCOPUS:84889795225

VL - 10

SP - 1886

EP - 1894

JO - Heart Rhythm

JF - Heart Rhythm

SN - 1547-5271

IS - 12

ER -