Investigation of the Causal Etiology in a Patient with T-B+NK+ Immunodeficiency
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PROVIDER: PRJNA856764 | ENA |
REPOSITORIES: ENA
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Project description:Investigation of the Causal Etiology in a Patient with T-B+NK+ Immunodeficiency
| PRJNA856765 | ENA
Project description: Not available
| S-EPMC9372720 | biostudies-literature
Project description:While monogenic variants in CDC45-MCM-GINS (CMG) replisome proteins cause human natural killer cell deficiencies (NKD), family members with the same inherited variants often have variable clinical and cellular phenotypes. Using iPSCs from two siblings with the same hereditary compound heterozygous GINS4 variants but variable disease expressivity, we modeled cell proliferation dynamics and the effect of GINS4 variants on NK cell development from pluripotent stem cells. Cell cycle impairment and increased apoptosis were detected in NK cells from patient-derived iPSCs following NK cell lineage commitment but not in pluripotent cells. While this effect was detected in cell lines from both siblings, the efficiency of NK cell differentiation was variable and correlated with differential clinical severity of NKD. Further investigation of allelic expression of inherited GINS4 variants demonstrated equal biallelic expression of GINS4 in pluripotent cells and primary CD34+ progenitors. However, allelic bias in lineage committed NK cells led to over- or under-representation of more damaging inherited GINS4 heterozygous variants that tracked with differential cellular and clinical severity. This study identifies allelic bias as an epigenetic factor that contributes to the phenotypic variations of monogenic diseases and further defines the etiology of NK cell-lineage specific immunodeficiency arising from CMG variants.
2025-06-27 | GSE267366 | GEO
Project description:While monogenic variants in CDC45-MCM-GINS (CMG) replisome proteins cause human natural killer cell deficiencies (NKD), family members with the same inherited variants often have variable clinical and cellular phenotypes. Using iPSCs from two siblings with the same hereditary compound heterozygous GINS4 variants but variable disease expressivity, we modeled cell proliferation dynamics and the effect of GINS4 variants on NK cell development from pluripotent stem cells. Cell cycle impairment and increased apoptosis were detected in NK cells from patient-derived iPSCs following NK cell lineage commitment but not in pluripotent cells. While this effect was detected in cell lines from both siblings, the efficiency of NK cell differentiation was variable and correlated with differential clinical severity of NKD. Further investigation of allelic expression of inherited GINS4 variants demonstrated equal biallelic expression of GINS4 in pluripotent cells and primary CD34+ progenitors. However, allelic bias in lineage committed NK cells led to over- or under-representation of more damaging inherited GINS4 heterozygous variants that tracked with differential cellular and clinical severity. This study identifies allelic bias as an epigenetic factor that contributes to the phenotypic variations of monogenic diseases and further defines the etiology of NK cell-lineage specific immunodeficiency arising from CMG variants.
2025-06-27 | GSE288864 | GEO
Project description:Inborn errors of immunity (IEI) result in increased morbidity and mortality from infections. However, discovering new IEIs is limited by the clinical identification of rare patient cohorts. To predict immunodeficiency-associated genes in a patient-independent approach, we performed a targeted CRISPR-Cas9 knockout screen in healthy human donor-derived PBMCs and identified myocyte enhancer factor 2C (MEF2C) as essential for primary human natural killer (NK) cell functionality ex vivo. MEF2C haploinsufficient (MCHS) patients and mice displayed impaired NK cell development, ex vivo function, and increased susceptibility to viral infection. MEF2C was required for cytokine-induced changes in NK cell metabolism and SREBP-mediated lipid homeostasis, and oleic acid supplementation restored MCHS patient NK cell cytotoxic function. Thus, we demonstrate a CRISPR-based methodology in primary human immune cells to accelerate the identification of new IEIs, and apply this approach to predict and validate a new NK cell immunodeficiency associated with metabolic and functional defects.
2024-03-11 | GSE245463 | GEO
Project description:A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism. We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID.
2025-04-29 | PXD063461 | Pride
Project description:More insights into the character differences between ChAT+ and ChAT- NK cells were obtained based on the gene-expression patterns. A clear delineation between ChAT+ NK cells and ChAT- NK cells was observed, with a total of 300 genes over-expressed and 941 genes under-expressed significantly in the ChAT+ subset. It will provide evidences for further investigation into their functional characters
2017-05-23 | GSE99126 | GEO
Project description:Myelofibrosis etiology and transplant outcomes
| PRJNA769154 | ENA
Project description:Myelofibrosis etiology and transplant outcomes
| PRJNA769155 | ENA
Project description:Investigation of the change of the Trail-dependent NK cell transcriptome during short-term (24h) infection with lymphocytic choriomeningitis virus (LCMV). RNA sequencing-based transcriptomics analysis was performed in spleen-isolated (NK1.1+CD3-) NK cells from 3 naïve Trail+/+ mice, 3 naive Trail-/- mice, 4 LCMV-infected Trail+/+ mice, and 4 LCMV-infected Trail-/- mice.
2019-08-27 | E-MTAB-7562 | biostudies-arrayexpress