A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation

Daniel C. Bartos, Jeffrey B. Anderson, Rachel Bastiaenen, Jonathan N. Johnson, Michael H. Gollob, David J. Tester, Don E. Burgess, Tessa Homfray, Elijah R. Behr, Michael John Ackerman, Pascale Guicheney, Brian P. Delisle

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

R231H Causes a High Penetrance for Familial AF Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease. Method and Results Candidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating. Conclusions The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF.

Original languageEnglish (US)
Pages (from-to)562-569
Number of pages8
JournalJournal of Cardiovascular Electrophysiology
Volume24
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

Penetrance
Atrial Fibrillation
Mutation
Action Potentials
Sudden Cardiac Death
KCNQ1 Potassium Channel
Syncope
Missense Mutation
Genetic Predisposition to Disease
Cardiac Arrhythmias
Incidence

Keywords

  • arrhythmia
  • atrial fibrillation
  • ion channels
  • KCNQ1
  • long-QT syndrome
  • potassium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Bartos, D. C., Anderson, J. B., Bastiaenen, R., Johnson, J. N., Gollob, M. H., Tester, D. J., ... Delisle, B. P. (2013). A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation. Journal of Cardiovascular Electrophysiology, 24(5), 562-569. https://doi.org/10.1111/jce.12068

A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation. / Bartos, Daniel C.; Anderson, Jeffrey B.; Bastiaenen, Rachel; Johnson, Jonathan N.; Gollob, Michael H.; Tester, David J.; Burgess, Don E.; Homfray, Tessa; Behr, Elijah R.; Ackerman, Michael John; Guicheney, Pascale; Delisle, Brian P.

In: Journal of Cardiovascular Electrophysiology, Vol. 24, No. 5, 05.2013, p. 562-569.

Research output: Contribution to journalArticle

Bartos, DC, Anderson, JB, Bastiaenen, R, Johnson, JN, Gollob, MH, Tester, DJ, Burgess, DE, Homfray, T, Behr, ER, Ackerman, MJ, Guicheney, P & Delisle, BP 2013, 'A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation', Journal of Cardiovascular Electrophysiology, vol. 24, no. 5, pp. 562-569. https://doi.org/10.1111/jce.12068
Bartos DC, Anderson JB, Bastiaenen R, Johnson JN, Gollob MH, Tester DJ et al. A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation. Journal of Cardiovascular Electrophysiology. 2013 May;24(5):562-569. https://doi.org/10.1111/jce.12068
Bartos, Daniel C. ; Anderson, Jeffrey B. ; Bastiaenen, Rachel ; Johnson, Jonathan N. ; Gollob, Michael H. ; Tester, David J. ; Burgess, Don E. ; Homfray, Tessa ; Behr, Elijah R. ; Ackerman, Michael John ; Guicheney, Pascale ; Delisle, Brian P. / A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation. In: Journal of Cardiovascular Electrophysiology. 2013 ; Vol. 24, No. 5. pp. 562-569.
@article{d3fa62e71d7642c7a6178dda0c3f4123,
title = "A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation",
abstract = "R231H Causes a High Penetrance for Familial AF Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease. Method and Results Candidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating. Conclusions The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF.",
keywords = "arrhythmia, atrial fibrillation, ion channels, KCNQ1, long-QT syndrome, potassium",
author = "Bartos, {Daniel C.} and Anderson, {Jeffrey B.} and Rachel Bastiaenen and Johnson, {Jonathan N.} and Gollob, {Michael H.} and Tester, {David J.} and Burgess, {Don E.} and Tessa Homfray and Behr, {Elijah R.} and Ackerman, {Michael John} and Pascale Guicheney and Delisle, {Brian P.}",
year = "2013",
month = "5",
doi = "10.1111/jce.12068",
language = "English (US)",
volume = "24",
pages = "562--569",
journal = "Journal of Cardiovascular Electrophysiology",
issn = "1045-3873",
publisher = "Wiley-Blackwell",
number = "5",

}

TY - JOUR

T1 - A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation

AU - Bartos, Daniel C.

AU - Anderson, Jeffrey B.

AU - Bastiaenen, Rachel

AU - Johnson, Jonathan N.

AU - Gollob, Michael H.

AU - Tester, David J.

AU - Burgess, Don E.

AU - Homfray, Tessa

AU - Behr, Elijah R.

AU - Ackerman, Michael John

AU - Guicheney, Pascale

AU - Delisle, Brian P.

PY - 2013/5

Y1 - 2013/5

N2 - R231H Causes a High Penetrance for Familial AF Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease. Method and Results Candidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating. Conclusions The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF.

AB - R231H Causes a High Penetrance for Familial AF Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease. Method and Results Candidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating. Conclusions The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF.

KW - arrhythmia

KW - atrial fibrillation

KW - ion channels

KW - KCNQ1

KW - long-QT syndrome

KW - potassium

UR - http://www.scopus.com/inward/record.url?scp=84876933197&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876933197&partnerID=8YFLogxK

U2 - 10.1111/jce.12068

DO - 10.1111/jce.12068

M3 - Article

VL - 24

SP - 562

EP - 569

JO - Journal of Cardiovascular Electrophysiology

JF - Journal of Cardiovascular Electrophysiology

SN - 1045-3873

IS - 5

ER -