1. Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.
- Author
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Blanco E, Camps C, Bahal S, Kerai MD, Ferla MP, Rochussen AM, Handel AE, Golwala ZM, Spiridou Goncalves H, Kricke S, Klein F, Zhang F, Zinghirino F, Evans G, Keane TM, Lizot S, Kusters MAA, Iro MA, Patel SV, Morris EC, Burns SO, Radcliffe R, Vasudevan P, Price A, Gillham O, Valdebenito GE, Stewart GS, Worth A, Adams SP, Duchen M, André I, Adams DJ, Santili G, Gilmour KC, Holländer GA, Davies EG, Taylor JC, Griffiths GM, Thrasher AJ, Dhalla F, and Kreins AY
- Subjects
- Humans, Male, Female, Endoplasmic Reticulum metabolism, Calcium Signaling, Infant, Child, Preschool, Child, Mutation, Missense, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency pathology, Severe Combined Immunodeficiency metabolism, Severe Combined Immunodeficiency immunology, Inositol 1,4,5-Trisphosphate Receptors metabolism, Inositol 1,4,5-Trisphosphate Receptors genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, Calcium metabolism
- 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., (© 2024 Blanco et al.)
- Published
- 2025
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