Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.

Nathalie Roux-Buisson; Marine Cacheux; Anne Fourest-Lieuvin; Jérémy Fauconnier; Julie Brocard; Isabelle Denjoy; Philippe Durand; Pascale Guicheney; Florence Kyndt; Antoine Leenhardt; Hervé Le Marec; Vincent Lucet; Philippe Mabo; Vincent Probst; Nicole Monnier; Pierre Ray; Elodie Santoni; Pauline Trémeaux; Alain Lacampagne; Julien Fauré; Joël Lunardi; Isabelle Marty

doi:10.1093/hmg/dds104

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.

Nathalie Roux-Buisson ¹ Marine Cacheux ² Anne Fourest-Lieuvin ³ Jérémy Fauconnier ⁴ Julie Brocard ² Isabelle Denjoy ⁵ Philippe Durand ⁶ Pascale Guicheney ⁷ Florence Kyndt ^{8, 9} Antoine Leenhardt ⁵ Hervé Le Marec ⁹ Vincent Lucet ¹⁰ Philippe Mabo ^{11, 12} Vincent Probst ⁹ Nicole Monnier ^{13, 14} Pierre Ray ^{15, 14} Elodie Santoni ¹⁴ Pauline Trémeaux ¹⁴ Alain Lacampagne ⁴ Julien Fauré ¹⁶ Joël Lunardi ¹⁶ Isabelle Marty ^{2, *}

* Auteur correspondant

1 INSERM U836, équipe 4, Muscles et pathologies

GIN - Grenoble Institut des Neurosciences, AGIM - AGeing and IMagery, Biochimie et Génétique Moléculaire

2 INSERM U836, équipe 4, Muscles et pathologies

GIN - Grenoble Institut des Neurosciences

3 INSERM U836, équipe 4, Muscles et pathologies

BIG - Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV), GIN - Grenoble Institut des Neurosciences

4 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]

5 Service de Cardiologie

6 Service de Réanimation Pédiatrique et Médecine Néonatale

7 Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires

8 Service de génétique médicale - Unité de génétique clinique [Nantes]

9 Institut du thorax

10 Unité de rythmologie pédiatrique

11 LTSI - Laboratoire Traitement du Signal et de l'Image

12 Service de cardiologie et maladies vasculaires

13 GIN - Grenoble Institut des Neurosciences

14 Biochimie et Génétique Moléculaire

15 AGIM - AGeing and IMagery

16 INSERM U836, équipe 4, Muscles et pathologies

GIN - Grenoble Institut des Neurosciences, Biochimie et Génétique Moléculaire

Abstract : Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans.

Type de document :

Article dans une revue

Human Molecular Genetics, Oxford University Press (OUP), 2012, 21 (12), pp.2759-67. 〈10.1093/hmg/dds104〉

Domaine :

Sciences du Vivant [q-bio] / Biochimie, Biologie Moléculaire

Liste complète des métadonnées

Littérature citée [35 références] Voir Masquer Télécharger

http://www.hal.inserm.fr/inserm-00763211
Contributeur : Nathalie Roux-Buisson <>
Soumis le : lundi 10 décembre 2012 - 12:15:52
Dernière modification le : jeudi 28 juin 2018 - 09:51:27
Document(s) archivé(s) le : lundi 11 mars 2013 - 12:20:37

RouxBuisson_2012_Absence_of_tr...

Fichiers éditeurs autorisés sur une archive ouverte

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.

Fichier

Identifiants

Collections

Citation

Exporter

Métriques

792

213

Contact

Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.

Fichier

Identifiants

Collections

Citation

Exporter

Partager

Métriques

792

213

Contact