title: Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.
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.
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Roux-Buisson
authors.forename: Marine
authors.initials: M
authors.lastname: Cacheux
authors.forename: Anne
authors.initials: A
authors.lastname: Fourest-Lieuvin
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Julie
authors.initials: J
authors.lastname: Brocard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Philippe
authors.initials: P
authors.lastname: Durand
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Florence
authors.initials: F
authors.lastname: Kyndt
authors.forename: Antoine
authors.initials: A
authors.lastname: Leenhardt
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.forename: Vincent
authors.initials: V
authors.lastname: Lucet
authors.forename: Philippe
authors.initials: P
authors.lastname: Mabo
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Nicole
authors.initials: N
authors.lastname: Monnier
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Ray
authors.forename: Elodie
authors.initials: E
authors.lastname: Santoni
authors.forename: Pauline
authors.initials: P
authors.lastname: Trémeaux
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Julien
authors.initials: J
authors.lastname: Fauré
authors.forename: Joël
authors.initials: J
authors.lastname: Lunardi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marty
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D016757:Death, Sudden, Cardiac; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D010375:Pedigree; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D002352:Carrier Proteins; D009124:Muscle Proteins; D020033:Protein Isoforms; C070048:triadin; D002118:Calcium