# Characterization and Treatment of Triadin Knockout Syndrome

> **NIH NIH F31** · MAYO CLINIC ROCHESTER · 2020 · $39,089

## Abstract

PROJECT SUMMARY
 Triadin knockout syndrome (TKOS) is a rare inherited cardiac arrhythmia disorder
caused by homozygous or compound heterozygous TRDN frameshift, nonsense, or missense
mutations which render patients effectively triadin null. TKOS has been characterized by either
consistent or transient QT prolongation, extensive T-wave inversions in the precordial leads,
and a severe disease expression of exercise induced syncope and cardiac arrest in early
childhood. Additionally, despite various treatment strategies such as beta blocker therapy and
left cardiac sympathetic denervation, the majority of patients have had recurrent breakthrough
cardiac events such as implantable cardioverter defibrillator shocks.
 Triadin is a critical component of the cardiac calcium release unit (CRU) complex where
the L-type calcium channel (LTCC) is juxtaposed to the calcium release channel (RyR2) on the
junctional sarcoplasmic reticulum (jSR). This complex is responsible for mediating calcium
sensing and proper excitation-contraction coupling (ECC) in the heart. Ablation of triadin causes
multiple structural and functional abnormalities in mice. Triadin knockout mice showed a
reduction in key proteins of the CRU including RyR2, Casq2, Jph2, and Jct. These mice also
exhibited a 50% reduction in LTCC co-localization to RyR2 which lead to loss of the negative
feedback loop on the LTCC, resulting in slow inactivation of the LTCC and SR calcium overload,
as well as ventricular arrhythmias, in the setting of β-adrenergic stimulation.
 While these previous studies have provided some insights into triadin’s role in the CRU,
this has never been examined in a human, triadin null cardiac cell model system. Therefore, it
remains unknown whether the insights drawn from the previous triadin null mouse studies can
be generalized to humans. For this reason, we propose to use human induced pluripotent stem
cell-derived cardiomyocytes (iPSC-CMs) generated from patients with TKOS as a novel cellular
model to characterize the disease and to establish the definitive pathophysiological mechanism
of TKOS in humans. In addition, we propose to assess the utility of adeno-associated virus
serotype 9 (AAV9)-mediated gene delivery of wild-type (WT) triadin to treat patient-specific iPS-
CMs, thus providing a proof-of-concept for an AAV9-mediated, gene-based therapy which could
be advanced further someday to more effectively treat patients with TKOS.

## Key facts

- **NIH application ID:** 9988001
- **Project number:** 1F31HL149131-01A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Daniel J Clemens
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,089
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-04-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988001

## Citation

> US National Institutes of Health, RePORTER application 9988001, Characterization and Treatment of Triadin Knockout Syndrome (1F31HL149131-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9988001. Licensed CC0.

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