Elena Blanco, Carme Camps, Sameer Bahal, Mohit D Kerai, Matteo P Ferla, Adam M Rochussen, Adam E Handel, Zainab M Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas M Keane, Sabrina Lizot, Maaike A A Kusters, Mildred A Iro, Sanjay V Patel, Emma C Morris, Siobhan O Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E Valdebenito, Grant S Stewart, Austen Worth, Stuart P Adams, Michael Duchen, Isabelle André, David J Adams, Giorgia Santili, Kimberly C Gilmour, Georg A Holländer, E Graham Davies, Jenny C Taylor, Gillian M Griffiths, Adrian J Thrasher, Fatima Dhalla, Alexandra Y Kreins
{"title":"Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.","authors":"Elena Blanco, Carme Camps, Sameer Bahal, Mohit D Kerai, Matteo P Ferla, Adam M Rochussen, Adam E Handel, Zainab M Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas M Keane, Sabrina Lizot, Maaike A A Kusters, Mildred A Iro, Sanjay V Patel, Emma C Morris, Siobhan O Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E Valdebenito, Grant S Stewart, Austen Worth, Stuart P Adams, Michael Duchen, Isabelle André, David J Adams, Giorgia Santili, Kimberly C Gilmour, Georg A Holländer, E Graham Davies, Jenny C Taylor, Gillian M Griffiths, Adrian J Thrasher, Fatima Dhalla, Alexandra Y Kreins","doi":"10.1084/jem.20220979","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6000,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577440/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1084/jem.20220979","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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