A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 ( ), ( ), and ( ) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical de novo variant-NM_002224.3:c.7570C>T, p.Arg2524Cys-causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4 lymphopenia, a quasi-absence of naïve CD4 and CD8 cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.