Abstract Text: The inositol 1,4,5 triphosphate receptors (ITPRs) span the endoplasmic reticulum, regulating intracellular calcium levels upon diverse receptor-ligand interactions. Three isoforms, ITPR1, ITPR2 and IPTR3 form homo- or hetero- tetramers, with autosomal recessive mutations in ITPR3 causing Charcot Marie Tooth disease. We identified 2 unrelated children with immunodeficiency and peripheral neuropathy who have the same de novo ITPR3 mutation. This ITPR3 variant (c.7570C>T) results in a p.Arg2524Cys substitution within the calcium pore. 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, low mitogen responses and depressed B cells. Small in stature, she 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 similar clinical presentations. 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. While T cell development appears normal based on cell numbers, early B cell development is severely attenuated. The data indicate that the single allelic Itpr3 mutation acts as a dominant negative protein. Notably, the targeting of ITPR3 could enable the two related ITPR family members to function normally, potentially improving immune, neuronal, and endocrine functions in the patients.
