Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans
Por:
Sun, B, Ni, MK, Li, YH, Song, ZP, Wang, H, Zhu, HL, Wei, JH, Belke, D, Cai, ST, Guo, WT, Yao, JJ, Tian, SS, Estillore, JP, Wang, RW, Sondergaard, MT, Brohus, M, Rohde, PD, Mu, YX, Vallmitjana, A, Benitez, R, Hove-Madsen, L, Overgaard, MT, Fishman, GI, Chen, J, Sanatani, S, Wilde, AAM, Fill, M, Ramos-Franco, J, Nyegaard, M, Chen, SRW
Publicada:
25 mar 2025
Resumen:
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.
Filiaciones:
Sun, B:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Kunming Univ Sci & Technol, Med Sch, Kunming 650500, Peoples R China
Ni, MK:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Li, YH:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan, Peoples R China
Song, ZP:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Wang, H:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Zhu, HL:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Wei, JH:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Belke, D:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Cai, ST:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Guo, WT:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Yao, JJ:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Tian, SS:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Estillore, JP:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Wang, RW:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Sondergaard, MT:
Aalborg Univ, Dept Chem & Biosci, Aalborg, Denmark
Brohus, M:
Aalborg Univ, Dept Chem & Biosci, Aalborg, Denmark
Rohde, PD:
Aalborg Univ, Dept Chem & Biosci, Aalborg, Denmark
Mu, YX:
Univ Calif San Diego, Dept Med, San Diego, CA 92161 USA
Vallmitjana, A:
Univ Politecn Cataluna, Dept Automat Control, Av Diagonal 647, E-08028 Barcelona, Spain
Benitez, R:
Univ Politecn Cataluna, Dept Automat Control, Av Diagonal 647, E-08028 Barcelona, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, Biomed Res Inst Barcelona IIBB, Spanish Natl Res Council CSIC, Barcelona, Spain
Hosp Santa Creu & Sant Pau, St Pau Biomed Res Inst IIB ST PAU, Barcelona, Spain
Fishman, GI:
New York Univ Langone Hlth, Leon H Charney Div Cardiol, New York, NY USA
Chen, J:
Univ Calif San Diego, Dept Med, San Diego, CA 92161 USA
Sanatani, S:
Univ British Columbia, Dept Pediat, Div Cardiol, Vancouver, BC, Canada
Wilde, AAM:
Univ Amsterdam, Med Ctr, Dept Cardiol, Ctr Heart,Locat Acad Med Ctr, Amsterdam, Netherlands
European Reference Network ERN GUARD Heart, Amsterdam, Netherlands
Fill, M:
Rush Univ Med Ctr, Dept Physiol & Biophys, Chicago, IL USA
Ramos-Franco, J:
Rush Univ Med Ctr, Dept Physiol & Biophys, Chicago, IL USA
Nyegaard, M:
Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark
Aarhus Univ, Dept Biomed, Aarhus, Denmark
Chen, SRW:
Univ Calgary, Libin Cardiovasc Inst, Dept Physiol & Pharmacol, 3280 Hosp Dr NW, Calgary, AB T2N 4N1, Canada
Rush Univ Med Ctr, Dept Physiol & Biophys, Chicago, IL USA
Green Accepted, Green Submitted, hybrid
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