Dominant negative variants in <i>ITPR3</i> impair T cell Ca2+ dynamics causing combined immunodeficiency

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2024-10-26
DOI
https://doi.org/10.1084/jem.20220979
Citations
10
Primary Topic
Ion Channels and Receptors
Type
article
Field-Weighted Citation Impact
3.61

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article

Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency

E. Graham Davies, Emma Morris, Sameer Bahal, Jenny C. Taylor et al.
10 citations
The Journal of Experimental Medicine
Ion Channels and Receptors
3.61
article

Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency

E. Graham Davies, Emma Morris, Sameer Bahal, Jenny C. Taylor, Siobhan O. Burns, Ruth Radcliffe, Adrian J. Thrasher, Pradeep Vasudevan, Michael R. Duchen, Gillian M. Griffiths, Adam M. Rochussen, Sabrina Lizot, Gabriel E. Valdebenito, Arthur Price, Mildred A. Iro, Alexandra Y. Kreins, Adam E. Handel, Zainab Golwala, Giorgia Santilli, Fatima Dhalla, Austen Worth, Stuart Adams, Thomas Keane, Grant S. Stewart, Olivia Gillham, Susanne Kricke, Federica Zinghirino, Fabian Klein, Maaike Kusters, Georg A. Holländer, Kimberly Gilmour, Matteo P. Ferla, Sanjay Patel, Isabelle André‐Schmutz, Fang Zhang, Elena Blanco, David J. Adams, Carme Camps, Grace Evans, Helena Spiridou Goncalves, Mohit D. Kerai
article en
10 citations

Abstract

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.

The Journal of Experimental MedicineVol. 222(1)
European Bioinformatics Institute (GB), Centre for Human Genetics (GB), Inserm (FR), University of Basel (CH), Université Paris Cité (FR), University of Cambridge (GB), Great Ormond Street Hospital (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), The Royal Free Hospital (GB), Royal London Hospital (GB), University Hospitals of Leicester NHS Trust (GB), Wellcome Sanger Institute (GB), University Hospital of Basel (CH), University Hospital Southampton NHS Foundation Trust (GB), National Institute for Health and Care Research (GB), ETH Zurich (CH), University of Oxford (GB), Oxford Biomedical Research (US), University Children’s Hospital Basel (CH), Department of Biomedicine Basel (CH), Regenerative Medicine Institute (MX), Oxford University Hospitals NHS Trust (GB), Institute of Infection and Immunity (CA), Institut des Maladies Génétiques Imagine (FR), University of Southampton (GB), University College London (GB), MRC Mitochondrial Biology Unit (GB), University of Birmingham (GB)
Fundación Alfonso Martín Escudero, Wellcome Trust, UK Research and Innovation, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Imperial College London, University College London, University of Oxford, Great Ormond Street Hospital Charity, Albert-Ludwigs-Universität Freiburg, Medical Research Council, Cambridge Institute for Medical Research, University of Cambridge, Great Ormond Street Institute of Child Health
Openalex Percentile: Top 6%
Ion Channels and Receptors
3.61
DOIOpen Access PDFOpenAlex
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