A human ITPR3 variant causes a dominant negative attenuation of calcium responses with immunodeficiency and growth delay confirmed in a mouse model

The inositol 1,4,5 triphosphate receptors (ITPRs) regulate intracellular calcium stores following diverse receptor-ligand interactions. Three iso-forms, ITPR1, ITPR2 and IPTR3 form homo- or hetero- tetramers in the ER that regulate calcium levels. Mutations in ITPR3 cause Charcot Marie Tooth disease. Two unrelated children who presented with immunodeficiency have the same de novo ITPR3 mutation. The ITPR3 variant (c.7570C>T) results in a single amino acid substitution (p.Arg2524Cys) within the calcium pore that is predicted to disrupt calcium release. Patient 1 is a 5 year old African-American female who had abnormal newborn screens for SCID. She has T cell deficiency, a predominance of memory T cells, and depressed B cells. Mitogen responses were low. She is small in stature, has conical deciduous teeth, anhidrosis, gait abnormalities and bilateral vocal fold paralysis. Nerve conduction studies (NCS) demonstrated sensorimotor polyneuropathy most prominent in lower extremities. Patient 2 is a 12 year old boy born to parents of Pakistani descent with a very similar clinical presentation as Patient 1.The ITPR3 mutation was genocopied in mice using CRISPR/Cas technologies. The Itpr3Wt/R2524C mice are significantly smaller than littermate controls with severe B cell immunodeficiency, reduced peripheral T cell numbers and impaired antigen-receptor induced calcium responses. The full details of the immune cell defects as well as eccrine and peripheral neuronal cell functions will be presented. Importantly, the data indicate that the single allelic Itpr3 mutation acts as a dominant negative, suggesting that the targeting of this gene will enable the two related Itpr family members to improve immune, neuronal and endocrine functions in the patients.