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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.).
Background:
Ca2+ mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca2+ handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca2+ handling and arrhythmia susceptibility.
Methods:
There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice).
Results:
We showed that the ITPR1-W1447G+/- and recently reported ITPR1-D2594K+/- GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca2+ and voltage imaging in situ in heart slices and Ca2+ imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G+/- and ITPR1-D2594K+/- variants increased the occurrence of stress-induced spontaneous Ca2+ release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF.
Conclusions:
Our studies in mice and humans reveal that enhanced function of ITPR1, a well-known movement disorder gene, increases the risk for cardiac arrhythmias.
Insights
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.
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.
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