Ablation of triadin causes loss of cardiac Ca
            <sup>2+</sup>
            release units, impaired excitation–contraction coupling, and cardiac arrhythmias

Chopra, Nagesh; Yang, Tao; Asghari, Parisa; Moore, Edwin D.W.; Huke, Sabine; Akin, Brandy L.; Cattolica, Robert Anthony; Pérez, Claudio F.; Hlaing, Thinn; Knollmann-Ritschel, Barbara; Jones, Larry R.; Pessah, Isaac N.; Allen, Paul D.; Franzini‐Armstrong, Clara; Knollmann, Björn C.

doi:10.1073/pnas.0902919106

Cited by 139 publications

(190 citation statements)

References 34 publications

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“…Comparison of the results reported in Figures 2A and 2B suggested that TD32 levels decreased due to the lack of functional CSQ2 from birth in the CSQ2-R33Q/R33Q mice. Results from a previous study (19) also showed that CSQ2 protein levels were significantly reduced in adult Trdn -/-mice. The mechanism of the post-transcriptional control of unfolded proteins can explain the reduction of CSQ2-R33Q protein levels without any effect on mRNA content.…”

Section: Discussionsupporting

confidence: 49%

Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

Bakiu

2014

Serbian Journal of Experimental and Clinical Research

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Section: Discussionsupporting

confidence: 49%

Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

Bakiu

2014

Serbian Journal of Experimental and Clinical Research

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“…In myocytes lacking triadin, junctional SR proteins (RyR2, Casq2, junctin and junctophilin) were decreased and Casq2 occurred outside of the junctional SR. [5] Additionally, electron micrographs showed reduced frequency of junctional SR cisternae and shorter RyR2 containing contacts, with a~50% reduction in contacts between the junctional SR and the t tubules [5]. Levels [5]. Further experiments in which SR Ca 2+ release was disabled (using the SR inhibitors ryanodine or thapsigargin) abolished differences in I CaL inactivation between wildtype and TRDN −/− myocytes, supporting this explanation [5].…”

Section: The Role Of Triadin-1 In Ventricular Myocytessupporting

confidence: 58%

“…In cardiac muscle, TRDN deletion has been reported to alter the structure of the CRU [5]. In myocytes lacking triadin, junctional SR proteins (RyR2, Casq2, junctin and junctophilin) were decreased and Casq2 occurred outside of the junctional SR. [5] Additionally, electron micrographs showed reduced frequency of junctional SR cisternae and shorter RyR2 containing contacts, with a~50% reduction in contacts between the junctional SR and the t tubules [5]. Levels [5].…”

Section: The Role Of Triadin-1 In Ventricular Myocytesmentioning

confidence: 99%

“…Experiments employing TRDN 'knockout' (KO) mice have provided insight into the roles of both skeletal muscle triadin isoforms [5,11,12]. Skeletal muscles from two different TRDN KO mice lines were found to show~30% of triads (structures formed by a t-tubule and adjacent terminal cisterna of the SR, either side of the t-tubule) in a longitudinal or oblique instead of transverse orientation and exhibited reduced Ca 2+ release [11,12].…”

Section: The Role Of Triadin-1 In Ventricular Myocytesmentioning

confidence: 99%

“…Whilst higher molecular weight isoforms can be detected in the heart, the predominant cardiac isoform is the Trisk 32 (32 kDa) isoform [4]. Accumulating evidence from recent mouse and human studies has implicated loss of functional triadin with heritable ventricular arrhythmia and risk of sudden death [2,[5][6][7][8]. Here we summarize briefly the evidence for involvement of TRDN mutations in human ventricular arrhythmia, discuss potential underlying mechanisms of arrhythmogenesis and summarize present and potential future treatment avenues.…”

Section: Introductionmentioning

confidence: 99%

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

Hancox

James

Walsh

et al. 2017

J Congenit Heart Dis

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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.

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Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome

Rabbani

Khorgami

Dalili

et al. 2021

American J of Med Genetics Pt A

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TRDN mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT) but may present with abnormal electrocardiogram (ECG) findings provoking a diagnosis of long QT syndrome (LQTS). We report two novel cases of sudden cardiac death in children due to mutations of TRDN, providing further insight into this rare and aggressive inherited arrhythmia syndrome. Whole exome sequencing (WES) was performed in two unrelated children who experienced cardiac arrest during exercise and were negative for targeted testing of LQTS. WES identified a novel homozygous splice‐site mutation in both patients, denoted c.22+1G>T, absent from gnomAD and suggesting a founder variant in the Iranian population. We now summarize the genetic architecture of all reported TRDN‐related patients, including 27 patients from 21 families. The average age‐onset was 30 months (range 1–10) for all cases. Adrenergic‐mediated cardiac events were common, occurring in 23 of 27 cases (85%). LQTS was diagnosed in 10 cases (37%), CPVT in 10 (37%) cases, and in 7 cases. No phenotypic diagnosis was provided. Five cases (15%) had evidence for associated skeletal myopathy. Four missense TRDN variants (24%) were observed in diseased cases, while the remaining variants reflect putative loss‐of‐function (LOF) mutations. No disease phenotype was reported in 26 heterozygous carriers. In conclusion, TRDN mutations cause a rare autosomal recessive arrhythmia syndrome presenting with adrenergic‐mediated arrhythmic events, but with ECG abnormalities leading to a diagnosis of LQTS in a proportion of cases. Heterozygous carriers are free of disease manifestations.

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Ablation of triadin causes loss of cardiac Ca ²⁺ release units, impaired excitation–contraction coupling, and cardiac arrhythmias

Cited by 139 publications

References 34 publications

Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

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

Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome

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Ablation of triadin causes loss of cardiac Ca 2+ release units, impaired excitation–contraction coupling, and cardiac arrhythmias

Cited by 139 publications

References 34 publications

Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

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

Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome

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Ablation of triadin causes loss of cardiac Ca ²⁺ release units, impaired excitation–contraction coupling, and cardiac arrhythmias