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      Is Open Access

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

      , 1 , 2 , 3 , 4 , 5 , 2 , 1 , 6 , 2 , 3 , 2 , 3 , 5 , 7 , 8 , 9 , 10 , 1 , 1 , 1 , 2 , 2 , 5 , 11 , 1 , 10 , 10 , 12 , 13 , 14 , 2 , 3 , 15 , 16 , 2 , 3 , 5 , 4 , , 2 , 3 , , 17 , , 1 , 18

      EMBO Molecular Medicine

      John Wiley and Sons Inc.

      Arrhythmia, CPVT, iPSC, LQTS, SRD5A2L2, Cardiovascular System, Genetics, Gene Therapy & Genetic Disease

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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 ([Ca 2+] i) dynamics in human induced pluripotent stem cell‐derived cardiomyocytes (hi PSCCMs) generated from this individual ( TECRL H om‐hi PSCs), his heterozygous but clinically asymptomatic father ( TECRL H et‐hi PSCs), and a healthy individual ( CTRL‐hi PSCs) from the same Sudanese family, revealed smaller [Ca 2+] i transient amplitudes as well as elevated diastolic [Ca 2+] i in TECRL H om‐hi PSCCMs compared with CTRL‐hi PSCCMs. The [Ca 2+] i transient also rose markedly slower and contained lower sarcoplasmic reticulum ( SR) calcium stores, evidenced by the decreased magnitude of caffeine‐induced [Ca 2+] i transients. In addition, the decay phase of the [Ca 2+] i transient was slower in TECRL H om‐hi PSCCMs due to decreased SERCA and NCX activities. Furthermore, TECRL H om‐hi PSCCMs showed prolonged action potentials ( APs) compared with CTRL‐hi PSCCMs. TECRL knockdown in control human embryonic stem cell‐derived CMs ( hESCCMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline ( NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations ( DADs) in TECRL H om‐hi PSCCMs 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 hi PSCCMs 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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          Most cited references 33

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          Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.

          Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.
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            Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans.

            Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited arrhythmia syndrome in which drug therapy is often ineffective. We discovered that flecainide prevents arrhythmias in a mouse model of CPVT by inhibiting cardiac ryanodine receptor-mediated Ca(2+) release and thereby directly targeting the underlying molecular defect. Flecainide completely prevented CPVT in two human subjects who had remained highly symptomatic on conventional drug therapy, indicating that this currently available drug is a promising mechanism-based therapy for CPVT.
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              Calcium fluxes involved in control of cardiac myocyte contraction.

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                Author and article information

                Contributors
                h.d.devalla@lumc.nl
                john.david.rioux@umontreal.ca
                z.a.bhuiyan@chuv.ch
                r.passier@lumc.nl
                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                24 October 2016
                December 2016
                : 8
                : 12 ( doiID: 10.1002/emmm.v8.12 )
                : 1390-1408
                Affiliations
                [ 1 ] Department of Anatomy & EmbryologyLeiden University Medical Center LeidenThe Netherlands
                [ 2 ]Montreal Heart Institute Montreal QCCanada
                [ 3 ] Department of MedicineUniversité de Montréal Montreal QCCanada
                [ 4 ] Department of Pediatrics College of Medicine and Health SciencesUAE University Al AinUnited Arab Emirates
                [ 5 ] Heart Failure Research Center Academic Medical CenterUniversity of Amsterdam AmsterdamThe Netherlands
                [ 6 ]Leiden University Medical Center hiPSC Core Facility LeidenThe Netherlands
                [ 7 ]Beijing Genomics Institute ShenzhenChina
                [ 8 ]Shenzhen Key Laboratory of Genomics ShenzhenChina
                [ 9 ]The Guangdong Enterprise Key Laboratory of Human Disease Genomics ShenzhenChina
                [ 10 ] Vital‐IT groupSwiss Institute of Bioinformatics LausanneSwitzerland
                [ 11 ] Service de CardiologieCentre Hospitalier Universitaire Vaudois (CHUV) LausanneSwitzerland
                [ 12 ] Institute of Social and Preventive MedicineUniversity Hospital (CHUV) and University of Lausanne LausanneSwitzerland
                [ 13 ] Laboratory of Experimental Cardiology Department of CardiologyLeiden University Medical Center LeidenThe Netherlands
                [ 14 ]ICIN‐Netherlands Heart Institute UtrechtThe Netherlands
                [ 15 ] Heart Center Department of Clinical and Experimental Cardiology Academic Medical CenterUniversity of Amsterdam AmsterdamThe Netherlands
                [ 16 ]Princess Al‐Jawhara Al‐Brahim Centre of Excellence in Research of Hereditary Disorders JeddahSaudi Arabia
                [ 17 ] Laboratoire Génétiqué MoléculaireCentre Hospitalier Universitaire Vaudois (CHUV) LausanneSwitzerland
                [ 18 ] Department of Applied Stem Cell Technologies MIRA Institute for Biomedical Technology and Technical MedicineUniversity of Twente EnschedeThe Netherlands
                Author notes
                [* ] Corresponding author. Tel: +31 715268889; E‐mail: h.d.devalla@ 123456lumc.nl

                Corresponding author. Tel: +1 5143763330 ext. 3741; E‐mail: john.david.rioux@ 123456umontreal.ca

                Corresponding author. Tel: +41 213143370; E‐mail: z.a.bhuiyan@ 123456chuv.ch

                Corresponding author. Tel: +31 534895553; E‐mail: r.passier@ 123456lumc.nl

                [†]

                These authors contributed equally to this work

                [‡]

                These authors contributed equally to this work

                Article
                EMMM201505719
                10.15252/emmm.201505719
                5167130
                27861123
                © 2016 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 8, Tables: 0, Pages: 19, Words: 11226
                Product
                Funding
                Funded by: Netherlands Organization for Health Research and Development
                Award ID: ZonMw‐TOP 40‐00812‐98‐12086
                Award ID: ZonMw‐MKMD‐40‐42600‐98‐036
                Funded by: European Research Council
                Award ID: STEMCARDIOVASC‐323182
                Funded by: Leenaards Foundation
                Funded by: Swiss Institute of Bioinformatics
                Funded by: Swiss National Science Foundation
                Award ID: 31003A‐143914
                Award ID: 51RTP0_151019
                Funded by: Fondation Suisse de Cardiologie
                Award ID: 29283
                Funded by: Netherlands CardioVascular Research Initiative
                Funded by: Dutch Federation of University Medical Centers
                Funded by: Royal Netherlands Academy of Sciences
                Funded by: Fondation de l'Institut de cardiologie de Montréal
                Funded by: University of Montreal
                Funded by: Hartstichting
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                emmm201505719
                December 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.0 mode:remove_FC converted:19.12.2016

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