Dominant negative variants in <i>ITPR3</i> impair T cell Ca2+ dynamics causing combined immunodeficiency
Elena Blanco, Carme Camps, Sameer Bahal, Mohit D. Kerai, Matteo P. Ferla, Adam M. Rochussen, Adam E. Handel, Zainab Golwala, Helena Spiridou Goncalves, Susanne Kricke, Fabian Klein, Fang Zhang, Federica Zinghirino, Grace Evans, Thomas Keane, Sabrina Lizot, Maaike Kusters, Mildred A. Iro, Sanjay Patel, Emma Morris, Siobhan O. Burns, Ruth Radcliffe, Pradeep Vasudevan, Arthur Price, Olivia Gillham, Gabriel E. Valdebenito, Grant S. Stewart, Austen Worth, Stuart Adams, Michael R. Duchen, Isabelle André‐Schmutz, David J. Adams, Giorgia Santilli, Kimberly Gilmour, Georg A. Holländer, E. Graham Davies, Jenny C. Taylor, Gillian M. Griffiths, Adrian J. Thrasher, Fatima Dhalla, Alexandra Y. Kreins
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.