Cellular and electrophysiological characterization of triadin knockout syndrome using induced pluripotent stem cell-derived cardiomyocytes

Stem Cell Reports. 2023 May 9;18(5):1075-1089. doi: 10.1016/j.stemcr.2023.04.005.

Abstract

Triadin knockout syndrome (TKOS) is a malignant arrhythmia disorder caused by recessive null variants in TRDN-encoded cardiac triadin. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from two unrelated TKOS patients and an unrelated control. CRISPR-Cas9 gene editing was used to insert homozygous TRDN-p.D18fs13 into a control line to generate a TKOS model (TRDN-/-). Western blot confirmed total knockout of triadin in patient-specific and TRDN-/- iPSC-CMs. iPSC-CMs from both patients revealed a prolonged action potential duration (APD) at 90% repolarization, and this was normalized by protein replacement of triadin. APD prolongation was confirmed in TRDN-/- iPSC-CMs. TRDN-/- iPSC-CMs revealed that loss of triadin underlies decreased expression and co-localization of key calcium handling proteins, slow and decreased calcium release from the sarcoplasmic reticulum, and slow inactivation of the L-type calcium channel leading to frequent cellular arrhythmias, including early and delayed afterdepolarizations and APD alternans.

Keywords: Arrhythmia; Calcium; Ion Channels; Stem Cells; Triadin; catecholaminergic polymorphic ventricular tachycardia; long QT syndrome; sudden cardiac death; triadin knockout syndrome.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials
  • Arrhythmias, Cardiac / pathology
  • Calcium / metabolism
  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Myocytes, Cardiac* / metabolism
  • Syndrome

Substances

  • triadin
  • Calcium