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
N1 - Funding Information:
Funding for this study from the following sources is gratefully acknowledged: the Netherlands Organization for Health Research and Development (ZonMw-TOP 40-00812-98-12086) to H.D.D and (ZonMw-MKMD-40-42600-98-036) to R.P; European Research Council advanced grant (STEMCARDIOVASC-323182) to C.L.M; the Leenaards Foundation, the Swiss Institute of Bioinformatics, and the Swiss National Science Foundation (31003A-143914, 51RTP0_151019) grants to Z.K; Fondation Suisse de Cardiologie (No. 29283) to Z.A.B; the Netherlands CardioVascular Research Initiative, the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PREDICT) to A.A.M.W; Fondation de l'Institut de cardiologie de Montréal to JDR; and the Phillipa and Marvin Carsley Chair of Medicine of the University of Montreal to MT and RT. The authors thank the following people for contributing to the research presented in this manuscript: Laura Robb and Dr Blandine Mondésert of the Cardiovascular Genetics Center of the Montreal Heart Institute for their assistance in the characterization of the French Canadian probands and family members; Prof. Jacques S. Beckmann for initiating the next-generation sequence study of the Sudanese family and incorporating this family for exome sequencing; Dr Tom van Wezel (Department of Pathology, LUMC) for helpful discussions; M. Ohtaka, K. Nishimura, and M. Nakanishi (National Institute of Advanced Industrial Science and Technology, Japan) for providing the Sendai virus vectors; S. van de Pas and A. ‘t Jong from the LUMC hiPSC core facility for support with reprogramming; D. de Jong, K. Szuhai, and H. Tanke (Department of Molecular Cell Biology, LUMC) for karyotyping, Verena Schwach (Department of Anatomy & Embryology, LUMC) for support with cell culture, and Annemarie Kip (Department of Cardiology, LUMC) for help with the lentiviral vector production. The computations were performed at the Vital-IT Center (http://www.vital-it.ch) for high-performance computing of the SIB Swiss Institute of Bioinformatics. The authors are especially grateful to the patient families for tissue samples and their consent for the study.
Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY 4.0 license
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 - LQTS
KW - SRD5A2L2
KW - iPSC
UR - http://www.scopus.com/inward/record.url?scp=84995745367&partnerID=8YFLogxK
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U2 - 10.15252/emmm.201505719
DO - 10.15252/emmm.201505719
M3 - Article
C2 - 27861123
AN - SCOPUS:84995745367
SN - 1757-4676
VL - 8
SP - 1390
EP - 1408
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
ER -