Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans
Abstract
BACKGROUND: Ca 2+ 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 2+ 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 2+ 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 2+ and voltage imaging in situ in heart slices and Ca 2+ 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 2+ 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.
Article Details
Authors (30)
Bo Sun
Mingke Ni
Department 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.).
Yanhui Li
School of Chemical Engineering and Technology, Key Laboratory for Green Chemical Technology of Ministry of Education, Tianjin University
Zhenpeng Song
Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary
Hui Wang
Hai-Lei Zhu
Department 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.).
Jinhong Wei
Darrell Belke
Department 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.).
Shitian Cai
Department 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.).
Wenting Guo
Jinjing Yao
Department 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.).
Shanshan Tian
Department 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.).
John Paul Estillore
Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary
Ruiwu Wang
Libin Cardiovascular Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary
Mads Toft Søndergaard
Department of Chemistry and Bioscience (M.T.S., M.B., P.D.R.), Aalborg University, Denmark.
Malene Brohus
Department of Chemistry and Bioscience (M.T.S., M.B., P.D.R.), Aalborg University, Denmark.
Palle Duun Rohde
Yongxin Mu
Department of Medicine, University of California at San Diego, La Jolla (Y.M., J.C.).
Alexander Vallmitjana
Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain (A.V., R.B.).
Raul Benitez
Leif Hove-Madsen
Michael Toft Overgaard
Glenn I. Fishman
Leon H. Charney Division of Cardiology, New York University Langone Health, New York, NY (G.I.F.).
Ju Chen
Shubhayan Sanatani
Children’s Heart Centre, BC Children’s Hospital, Vancouver, BC, Canada (S.S.)
Arthur A.M. Wilde
Heart Center, Department of Cardiology, Amsterdam Cardiovascular Sciences Heart Failure & Arrhythmias, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands (R.E.K., L.A.D., A.-F.B.E.Q., T.F.B., A.d.W., N.R.B., W.v.d.S., J.A.d.V., K.M.K., S.P., A.A.M.W., L.R.A.O.N., L.S., L.V.A.B.).
Michael Fill
Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL (M.F., J.R.-F., S.R.W.C.).
Josefina Ramos-Franco
Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL (M.F., J.R.-F., S.R.W.C.).
Mette Nyegaard
S.R. Wayne Chen
Department 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.).