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Related Experiment Video

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Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and

Bo Sun1,2, Mingke Ni1, Yanhui Li1,3

  • 1Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Canada (B.S., M. Ni, Y.L., Z.S., H.W., H.-L.Z., J.W., D.B., S.C., W.G., J.Y., S.T., J.P.E., R.W., S.R.W.C.).

Circulation
|December 10, 2024
PubMed
Summary
This summary is machine-generated.

Enhanced inositol 1,4,5-trisphosphate receptor 1 (ITPR1) function, previously linked to movement disorders, increases cardiac arrhythmia risk. This study identified gain-of-function ITPR1 variants and demonstrated their role in stress-induced arrhythmias in mice and humans.

Keywords:
Purkinje cellscardiac ryanodine receptorinositol 1,4,5-trisphosphate receptorsarcoplasmic reticulumspontaneous Ca2+ releasetriggered activityventricular arrhythmias

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Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Calcium (Ca2+) mishandling in cardiac Purkinje cells is a known cause of arrhythmias.
  • Inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is crucial for Ca2+ handling in Purkinje cells.
  • While loss-of-function ITPR1 variants cause neurological disorders, the role of ITPR1 gain-of-function (GOF) in cardiac arrhythmias remains unclear.

Purpose of the Study:

  • To identify human ITPR1 GOF variants.
  • To determine the impact of ITPR1 GOF on Ca2+ handling and arrhythmia susceptibility.

Main Methods:

  • Characterized 33 human ITPR1 missense variants from open databases, identifying 21 GOF variants.
  • Generated a mouse model (ITPR1-W1457G) expressing a human ITPR1 GOF variant.
  • Analyzed UK Biobank data for associations between rare ITPR1 variants and cardiac arrhythmias.

Main Results:

  • ITPR1-W1447G+/- and ITPR1-D2594K+/- mutant mice exhibited susceptibility to stress-induced ventricular arrhythmias.
  • ITPR1 GOF variants in Purkinje cells increased spontaneous Ca2+ release, delayed afterdepolarizations, and triggered activity.
  • Seven rare ITPR1 missense variants associated with cardiac arrhythmias in humans were identified, all exhibiting GOF in vitro.

Conclusions:

  • Enhanced ITPR1 function, a known movement disorder gene, elevates the risk for cardiac arrhythmias.
  • ITPR1 GOF variants contribute to arrhythmogenesis through altered Purkinje cell Ca2+ handling.
  • This research links ITPR1 GOF to cardiac arrhythmia susceptibility in both mouse models and human populations.