TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT

Harsha D. Devalla, Roselle Gélinas, Elhadi H. Aburawi, Abdelaziz Beqqali, Philippe Goyette, Christian Freund, Marie A. Chaix, Rafik Tadros, Hui Jiang, Antony Le Béchec, Jantine J. Monshouwer-Kloots, Tom Zwetsloot, Georgios Kosmidis, Frédéric Latour, Azadeh Alikashani, Maaike Hoekstra, Jurg Schlaepfer, Christine L. Mummery, Brian Stevenson, Zoltan Kutalik & 9 others Antoine A.F. de Vries, Léna Rivard, Arthur A.M. Wilde, Mario Talajic, Arie O. Verkerk, Lihadh Al-Gazali, John D. Rioux, Zahurul A. Bhuiyan, Robert Passier

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Abstract

Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLH om-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLH et-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRLH om-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]i transients. In addition, the decay phase of the [Ca2+]i transient was slower in TECRLH om-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRLH om-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLH om-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.

Original languageEnglish
Pages (from-to)1390-1408
Number of pages19
JournalEMBO molecular medicine
Volume8
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016

Fingerprint

Induced Pluripotent Stem Cells
Cardiac Arrhythmias
Cardiac Myocytes
Genes
Flecainide
Action Potentials
Fatty Acid Desaturases
Exome
Calcium
Induced Heart Arrest
Mutation
Preclinical Drug Evaluations
Polymorphic catecholergic ventricular tachycardia
Anti-Arrhythmia Agents
Sudden Cardiac Death
Sarcoplasmic Reticulum
Ventricular Tachycardia
Caffeine
Fathers
Adrenergic Agents

Keywords

  • Arrhythmia
  • CPVT
  • iPSC
  • LQTS
  • SRD5A2L2

Cite this

Devalla, Harsha D. ; Gélinas, Roselle ; Aburawi, Elhadi H. ; Beqqali, Abdelaziz ; Goyette, Philippe ; Freund, Christian ; Chaix, Marie A. ; Tadros, Rafik ; Jiang, Hui ; Le Béchec, Antony ; Monshouwer-Kloots, Jantine J. ; Zwetsloot, Tom ; Kosmidis, Georgios ; Latour, Frédéric ; Alikashani, Azadeh ; Hoekstra, Maaike ; Schlaepfer, Jurg ; Mummery, Christine L. ; Stevenson, Brian ; Kutalik, Zoltan ; de Vries, Antoine A.F. ; Rivard, Léna ; Wilde, Arthur A.M. ; Talajic, Mario ; Verkerk, Arie O. ; Al-Gazali, Lihadh ; Rioux, John D. ; Bhuiyan, Zahurul A. ; Passier, Robert. / TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. In: EMBO molecular medicine. 2016 ; Vol. 8, No. 12. pp. 1390-1408.
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abstract = "Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLH om-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLH et-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRLH om-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]i transients. In addition, the decay phase of the [Ca2+]i transient was slower in TECRLH om-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRLH om-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLH om-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.",
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Devalla, HD, Gélinas, R, Aburawi, EH, Beqqali, A, Goyette, P, Freund, C, Chaix, MA, Tadros, R, Jiang, H, Le Béchec, A, Monshouwer-Kloots, JJ, Zwetsloot, T, Kosmidis, G, Latour, F, Alikashani, A, Hoekstra, M, Schlaepfer, J, Mummery, CL, Stevenson, B, Kutalik, Z, de Vries, AAF, Rivard, L, Wilde, AAM, Talajic, M, Verkerk, AO, Al-Gazali, L, Rioux, JD, Bhuiyan, ZA & Passier, R 2016, 'TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT' EMBO molecular medicine, vol. 8, no. 12, pp. 1390-1408. https://doi.org/10.15252/emmm.201505719

TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. / Devalla, Harsha D.; Gélinas, Roselle; Aburawi, Elhadi H.; Beqqali, Abdelaziz; Goyette, Philippe; Freund, Christian; Chaix, Marie A.; Tadros, Rafik; Jiang, Hui; Le Béchec, Antony; Monshouwer-Kloots, Jantine J.; Zwetsloot, Tom; Kosmidis, Georgios; Latour, Frédéric; Alikashani, Azadeh; Hoekstra, Maaike; Schlaepfer, Jurg; Mummery, Christine L.; Stevenson, Brian; Kutalik, Zoltan; de Vries, Antoine A.F.; Rivard, Léna; Wilde, Arthur A.M.; Talajic, Mario; Verkerk, Arie O.; Al-Gazali, Lihadh; Rioux, John D.; Bhuiyan, Zahurul A.; Passier, Robert.

In: EMBO molecular medicine, Vol. 8, No. 12, 01.12.2016, p. 1390-1408.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT

AU - Devalla, Harsha D.

AU - Gélinas, Roselle

AU - Aburawi, Elhadi H.

AU - Beqqali, Abdelaziz

AU - Goyette, Philippe

AU - Freund, Christian

AU - Chaix, Marie A.

AU - Tadros, Rafik

AU - Jiang, Hui

AU - Le Béchec, Antony

AU - Monshouwer-Kloots, Jantine J.

AU - Zwetsloot, Tom

AU - Kosmidis, Georgios

AU - Latour, Frédéric

AU - Alikashani, Azadeh

AU - Hoekstra, Maaike

AU - Schlaepfer, Jurg

AU - Mummery, Christine L.

AU - Stevenson, Brian

AU - Kutalik, Zoltan

AU - de Vries, Antoine A.F.

AU - Rivard, Léna

AU - Wilde, Arthur A.M.

AU - Talajic, Mario

AU - Verkerk, Arie O.

AU - Al-Gazali, Lihadh

AU - Rioux, John D.

AU - Bhuiyan, Zahurul A.

AU - Passier, Robert

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLH om-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLH et-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRLH om-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]i transients. In addition, the decay phase of the [Ca2+]i transient was slower in TECRLH om-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRLH om-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLH om-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.

AB - Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLH om-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLH et-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRLH om-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]i transients. In addition, the decay phase of the [Ca2+]i transient was slower in TECRLH om-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRLH om-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLH om-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.

KW - Arrhythmia

KW - CPVT

KW - iPSC

KW - LQTS

KW - SRD5A2L2

UR - http://www.scopus.com/inward/record.url?scp=84995745367&partnerID=8YFLogxK

U2 - 10.15252/emmm.201505719

DO - 10.15252/emmm.201505719

M3 - Article

VL - 8

SP - 1390

EP - 1408

JO - EMBO molecular medicine

JF - EMBO molecular medicine

SN - 1757-4676

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ER -