A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.

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 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 ami

SUBMITTER: Molitor A 

PROVIDER: S-EPMC11397499 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature