Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional Inositol 1,4,5-trisphosphate receptor subtype 3 defects

Calcium signaling is essential for lymphocyte activation, with genetic disruptions resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP 3 R), formed from homo- or hetero-tetramers of the IP 3 R isoforms 1-3, amplifies lymphocyte signaling by releasing Ca 2+ from ER stores into the cytosol following antigen-stimulation. While knockout of all 3 IP 3 R isoforms results in immunodeficiency in mice, the seeming redundancy of subunits was thought to explain the absence of IP 3 R mutation as a cause of human immunodeficiency. Here, we identify compound heterozygous variants in ITPR3 in two unrelated Caucasian patients presenting with combined immunodeficiency, in one case requiring hematopoietic stem cell transplantation. We observed disrupted Calcium homeostasis in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following B and T cell receptor stimulation. Reconstitution of IP 3 R knockout cell lines identified the variants as functional hypomorphs with reduced discrimination between homeostatic and induced states, validating a link between genotype and phenotype. These results demonstrate a functional linkage between defective ER Ca 2+ channels and immunodeficiency, and identify IP 3 Rs as diagnostic targets for patients with specific inborn errors of immunity.