biostudies-literatureBlanco ELetterOneCancer Research UKGreat Ormond Street Hospital Children's CharityBiomedical Research CentreMedical Research CouncilUniversity College LondonUCL Capital Equipment FundingFundación Alfonso Martín EscuderoNational Institute for Health and Care ResearchWellcome TrustUK Research and InnovationGreat Ormond Street Hospital Children's Charitye20220979https://www.ebi.ac.uk/biostudies/studies/S-EPMC11577440biostudies-literatureUnknown222(1)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 sThe Journal of experimental medicineDominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.PMC11577440203141/Z/16/ZU09822MR/L012758/1MR/S021930/1203141/Z/16/Z, 217112/Z/19/Z, 222096/Z/20/Z23303217112/Z/19/Z222096/Z/20/ZZhang FValdebenito GESantili GTaylor JCRochussen AMBurns SOKerai MDDavies EGStewart GSDuchen MBahal SAdams SPMorris ECRadcliffe RPatel SVAdams DJGriffiths GMFerla MPBlanco EVasudevan PZinghirino FGolwala ZMLizot SIro MAEvans GGillham ODhalla FCamps CHandel AEGilmour KCSpiridou Goncalves HKeane TMWorth AKlein FThrasher AJKusters MAAAndre IPrice AKricke SHollander GAKreins AYfalseDominant negative variants in ITPR3 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 s2025-01-01T00:00:00Z2025 Jan2026-06-03T01:08:20.238Z2026-04-22T03:11:46.092ZS-EPMC115774403956067310.1084/jem.20220979