RNA transcript changes in Itpr3 p.R2523C Effector Memory CD4+ T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE332595 | GEO | 2026/05/21
REPOSITORIES: GEO
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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:Messenger (m)RNA export from the nucleus is essential for eukaryotic gene expression. Here, we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export. IPMK depletion or catalytic inactivation selectively decreases the nuclear export of RAD51 mRNA, and RAD51 protein abundance, thereby impairing HR. Recognition of a sequence motif in the untranslated region of RAD51 transcripts by the mRNA export factor ALY requires IPMK. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), an IPMK product, restores ALY recognition in IPMK-depleted cell extracts, suggesting a mechanism underlying transcript selection. Our findings implicate IPMK in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans. We used gene expression profiling to compare the abundance of cytoplasmic RNAs after IPMK depletion
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Project description:Messenger (m)RNA export from the nucleus is essential for eukaryotic gene expression. Here, we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export. IPMK depletion or catalytic inactivation selectively decreases the nuclear export of RAD51 mRNA, and RAD51 protein abundance, thereby impairing HR. Recognition of a sequence motif in the untranslated region of RAD51 transcripts by the mRNA export factor ALY requires IPMK. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), an IPMK product, restores ALY recognition in IPMK-depleted cell extracts, suggesting a mechanism underlying transcript selection. Our findings implicate IPMK in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans.
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Project description:Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) is a molecule enriched in the brain and neurons that regulates intracellular calcium levels via signaling through the inositol trisphosphate receptor. In the present study, we found that IP3K-A expression is highly enriched in the central nucleus of the amygdala (CeA), which plays a pivotal role in the processing and expression of emotional phenotypes in mammals. We used microarray to identify differentially expressed genes in the amydala of wild type (WT) and IP3K-A KO mice. Male IP3K-A KO mice and their wild-type (WT) littermate controls from a C57BL/6N background were used at 10 to 15 weeks old. Mice were housed in temperature (22°C-23°C)- and humidity (50%)-controlled quarters under a 12-hr light/dark photoperiod (lights on at 08:00a.m.) with free access to food and water. Mice were sacrificed by cervical dislocation between 02:00p.m. and 04:00p.m. Amygdala tissue was rapidly dissected from 1-mm thick slices and frozen in liquid nitrogen.
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