Triadin mutations - a cause of ventricular arrhythmias in children and young adults

Abstract

Triadin-1, encoded by TRDN, is an important component of the calcium release unit (CRU) in the sarcoplasmic reticulum of cardiac myocytes, interacting both with ryanodine receptors and calsequestrin. This article reviews evidence substantiating a link between TRDN mutations and potentially fatal ventricular arrhythmias. Evidence from mouse TRDN knockout models indicates structural and functional changes to the cardiac myocyte CRU in the absence of triadin that result in disturbed Ca 2+ handling and susceptibility to adrenergic agonist provoked arrhythmias. In particular, cellular electrophysiology experiments have provided evidence of reduced Ca 2+ induced inactivation of L-type Ca 2+ channels consequent to TRDN knockout. A number of reports since 2012 have identified patients with a CPVT phenotype, some of whom also exhibit prolonged QT c intervals, with TRDN mutations. Symptomatic patients have homozygous or compound heterozygous mutations predicted to result in absent or nonfunctional triadin. Typically they have experienced serious ventricular arrhythmias or cardiac arrest at a very young age against a background of exertion, excitement or stress. Some patients have also shown skeletal muscle weakness. β adrenoceptor blockers, particularly nadolol, have been used successfully in some patients, though others have continued to experience cardiac events. Implantable devices have been critically important in cardioverting episodes of ventricular fibrillation in a number of patients. Flecainide has been successful at reducing the burden on implantable devices in two patients. Potential future additional/alternative pharmacological treatments include L-type Ca 2+ channel blockers, the class Ic antiarrhythmic propafenone and the β adrenoceptor blocker carvedilol. The potential value of such strategies should be explored using appropriate in vitro and in vivo models. In conclusion, triadin knockout syndrome is inherited in an autosomal recessive fashion and should be considered in cases of CPVT or Long QT Syndrome in which mutations to ion channels/transporters are not found. It should be particularly, though not exclusively, suspected in cases with concomitant muscle weakness. Further work is required to identify optimal therapeutic strategies.

Re-evaluation of single nucleotide variants and identification of structural variants in a cohort of 45 sudden unexplained death cases

“…Triadin-1, encoded by TRDN, is an important component of the calcium release unit in the sarcoplasmic reticulum of cardiac myocytes and a number of variants have been identified in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) [43].…”

A unique triadin exon deletion causing a null phenotype

“…C: Dashed lines show that components of TRDN missing in our patient, which will result in the inability of the protein to interact with CASQ2 and RYR2, and inability to anchor in the membrane of the sarcoplasmic reticulum (SR). 14 …”

Triadin-Antisense: An lncRNA in the Backstage of Cardiac Alternative Splicing

“…Globally, the phenotype of Trdn-as KO mice resembles the calcium-handling defects observed in Trdn KO mice 11 and in patients with the triadin KO syndrome. 12 The cardiac isoform of triadin, triadin-1, was greatly reduced in Trdn-as KO mice. Triadin-1 overexpression was sufficient to rescue the Ca 2+ -handling defects.…”