A pleiotropic recurrent dominant <i>ITPR3</i> variant causes a complex multisystemic disease.

Abstract

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (<i>ITPR1</i>), <i>2</i> (<i>ITPR2</i>), and <i>3</i> (<i>ITPR3</i>) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical <i>ITPR3</i> 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 Arg²⁵²⁴ 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 <i>ITPR1-3</i> deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant <i>ITPR3</i> variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.