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A single recurrent dominant variant in ITPR3 leads to a syndromic immunodeficiency

ABSTRACT: A single recurrent dominant variant in ITPR3 leads to a syndromic immunodeficiency

PROVIDER: PRJEB63615 | ENA |

REPOSITORIES: ENA

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A single recurrent dominant variant in ITPR3 leads to a syndromic immunodeficiency

Project description:Intracellular calcium levels are finely tuned through intricate actions of a number of channels and transporters, including those at key endocellular stores, e.g. endoplasmic reticulum (ER), lysosomes, and mitochondria. Along with the highly homologous genes Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1) and 2 (ITPR2), ITPR3 encodes the IP3 receptor (IP3R), a key player in intracellular calcium release in animals. Here we report the first cases of ITPR3 defects in man leading to a primarily dysimmune phenotype. In four unrelated patients of diverse ethnicity, and suffering from a complex immunodeficiency syndrome, we report the same de novo pathogenic variant - c.7570C>T; p.Arg2524Cys - in ITPR3. Clinically, recurrent severe infectious episodes of viral and bacterial origins, features of ectodermal dysplasia and that of Charcot-Marie-Tooth disease were paramount. The identified variant does not affect gene transcription, yet it was structurally predicted and biologically proven to disrupt proper protein folding and function in vivo. This eventually leads to defective Calcium flux in patient cells, dysregulation of mitochondrial function and a broad dysimmune phenotype characterized primarily by a profound CD4 T cell lymphopenia associated with quasi absence of naïve CD4 and CD8 cells, itself mirrored by an increase in cognate memory cells. The Calcium signaling defect was recapitulated ex vivo through the introduction of this single variant in Jurkat cells. Moreover, site-directed mutagenesis displayed the exquisite sensitivity of Arg2524 to any amino acid change. In conclusion, a single unique recurrent de novo variant in ITPR3 leads to a novel syndromic immunodeficiency.

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Project description:This study reports two unrelated patients with a combined immunodeficiency. Whole-exome sequencing of both patients, their healthy parents and siblings identified in both families a /de novo/ missense variant in /ITPR3/ (NM_002224.3:c.7570C>T, p.Arg2524Cys). While the mRNA level in patients remained the same as in healthy siblings and controls, the level of protein expression was diminished. It was also shown that the ITPR3 heterozygous p.Arg2524Cys mutation impairs calcium flux function in dermal fibroblast of one patient and in a knock-in Jurkat T cell line.

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Project description:This study reports two unrelated patients with a combined immunodeficiency. Whole-exome sequencing of both patients, their healthy parents and siblings identified a single de novo missense variant in ITPR3 (NM_002224.3:c.7570C>T, p.Arg2524Cys) in both index cases. While the mRNA level in patients remained the same as in healthy siblings and controls, the level of protein expression was diminished. It was also shown that the ITPR3 heterozygous p.Arg2524Cys mutation impairs calcium flux function in dermal fibroblast of one patient and in a knock-in Jurkat T cell line. Two additional patients with related phenotypes and the same mutation were further identified and described in the study. The present dataset corresponds to the RNAseq performed on PBMC of patient 2 of the study and healthy controls.

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Project description:Here we compare the transcriptional profiles of SW480 cells with ITPR3 or RELB knockout with control cells under normoxia and hypoxia.

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