Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans
Sun, B. (Kunming University of Science and Technology)
Ni, M. (University of Calgary)
Li, Yuda (Huazhong University of Science and Technology)
Song, Z. (University of Calgary)
Wang, H. (University of Calgary)
Zhu, H.L. (University of Calgary)
Wei, J. (University of Calgary)
Belke, D. (University of Calgary)
Cai, S. (University of Calgary)
Guo, W. (University of Calgary)
Yao, J. (University of Calgary)
Tian, S. (University of Calgary)
Estillore, J.P. (University of Calgary)
Wang, Rui (University of Calgary)
Søndergaard, M.T. (Aalborg Universitet)
Brohus, M. (Aalborg Universitet)
Rohde, P.D. (Aalborg Universitet)
Mu, Y. (Department of Medicine. University of California at San Diego)
Vallmitjana, A. (Universitat Politècnica de Catalunya)
Benítez, Raúl (Universitat Politècnica de Catalunya)
Madsen, Leif Hove (Institut de Recerca Sant Pau)
Overgaard, M.T.
Fishman, G.I. (New York University Langone Health)
Chen, Ju (University of California at San Diego)
Sanatani, S. (University of British Columbia)
Wilde, A.A.M. (European Reference Network Ern GUARD-heart)
Fill, M. (Rush University Medical Center)
Ramos-Franco, J. (Rush University Medical Center)
Nyegaard, M. (Aarhus University)
Chen, S.R.W. (University of Calgary)
Universitat Autònoma de Barcelona

Fecha:	2025
Resumen:	BACKGROUND: Ca 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 Ca 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 Ca 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 Ca and voltage imaging in situ in heart slices and Ca imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G and ITPR1-D2594K variants increased the occurrence of stress-induced spontaneous Ca 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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Purkinje cells ; Cardiac ryanodine receptor ; Inositol 1,4,5-trisphosphate receptor ; Sarcoplasmic reticulum ; Spontaneous Ca2+ release ; Triggered activity ; Ventricular arrhythmias
Publicado en:	Circulation, Vol. 151 Núm. 12 (25 2025) , p. 847-862, ISSN 1524-4539

DOI: 10.1161/CIRCULATIONAHA.124.070563
PMID: 39655431

16 p, 12.9 MB

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