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Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2012 Jun 15; Vol. 21 (12), pp. 2759-67. Date of Electronic Publication: 2012 Mar 14. - Publication Year :
- 2012
-
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.
- Subjects :
- Animals
Arrhythmias, Cardiac metabolism
Blotting, Western
COS Cells
Calcium metabolism
Carrier Proteins metabolism
Cell Membrane metabolism
Chlorocebus aethiops
Endoplasmic Reticulum metabolism
Family Health
Female
Genes, Recessive
Genetic Predisposition to Disease genetics
Humans
Male
Mice
Mice, Knockout
Muscle Proteins metabolism
Mutation
Myocytes, Cardiac metabolism
Pedigree
Protein Isoforms genetics
Protein Isoforms metabolism
Rats
Reverse Transcriptase Polymerase Chain Reaction
Tachycardia, Ventricular metabolism
Tachycardia, Ventricular pathology
Arrhythmias, Cardiac genetics
Carrier Proteins genetics
Death, Sudden, Cardiac
Muscle Proteins genetics
Tachycardia, Ventricular genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 21
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 22422768
- Full Text :
- https://doi.org/10.1093/hmg/dds104