Blanco, Elena;
Camps, Carme;
Bahal, Sameer;
Kerai, Mohit D;
Ferla, Matteo P;
Rochussen, Adam M;
Handel, Adam E;
... Kreins, Alexandra Y; + view all
(2024)
Dominant negative variants in ITPR3 impair T cell
Ca2+ dynamics causing combined immunodeficiency.
Journal of Experimental Medicine (JEM)
, 222
(1)
, Article e20220979. 10.1084/jem.20220979.
Preview |
Text
Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.pdf - Published Version Download (6MB) | Preview |
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.
Archive Staff Only
 |
View Item |
