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

Julika Neumann, Erika van Nieuwenhove, Lara E Terry, Frederik Staels, Taylor R Knebel, Kirsten Welkenhuyzen, Mariah R Baker, Margaux Gerbaux, Mathijs Willemsen, John S Barber, Irina I Serysheva, Liesbeth De Waele (+7 others)
2021 medRxiv   pre-print

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Calcium signaling is essential for lymphocyte activation, with genetic disruptions resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP3R), formed from homo- or hetero-tetramers of the IP3R isoforms 1-3, amplifies lymphocyte signaling by releasing Ca2+ from ER stores into the cytosol following antigen-stimulation. While knockout of all 3 IP3R isoforms results in immunodeficiency in mice, the seeming redundancy of subunits was thought to explain the absence of IP3R
more » ... 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 IP3R 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 Ca2+ channels and immunodeficiency, and identify IP3Rs as diagnostic targets for patients with specific inborn errors of immunity.
doi:10.1101/2021.05.29.21257775 fatcat:kge33s63arhffit47ppobp2qwu
Citation

Julika Neumann, Erika van Nieuwenhove, Lara E Terry, Frederik Staels, Taylor R Knebel, Kirsten Welkenhuyzen, Mariah R Baker, Margaux Gerbaux, Mathijs Willemsen, John S Barber, Irina I Serysheva, Liesbeth De Waele, Francois Vermeulen, Isabelle Meyts, David I Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston. "Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional Inositol 1,4,5-trisphosphate receptor subtype 3 defects." medRxiv (2021)