A Pleiotropic Recurrent Dominant Itpr3 Variant Causes a Complex Multisystemic Disease Publisher Pubmed



Molitor A^{1, 2} ; Lederle A^{1, 2} ; Radosavljevic M^{1, 2, 3} ; Sapuru V^{4, 5} ; Zavorka Thomas ME⁶ ; Yang J^{1, 2} ; Shirin M^{1, 2} ; Collinbund V^{1, 2} ; Jerabkovaroda K^{1, 7} ; Miao Z^{8, 9} ; Bernard A^{1, 2, 3} ; Rolli V^{1, 2, 3} ; Grenot P^{1, 2} ; Castro CN¹⁰ Show All Authors
Source: Science Advances Published:2024

Abstract

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1), 2 (ITPR2), and 3 (ITPR3) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 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 naive 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 ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex. © 2024 American Association for the Advancement of Science. All rights reserved.