Ontology highlight
ABSTRACT:
PROVIDER: PRJNA913788 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22806354_1.fastq.gz | Fastqsanger.gz | |||
| SRR22806354_2.fastq.gz | Fastqsanger.gz | |||
| SRR22806355_1.fastq.gz | Fastqsanger.gz | |||
| SRR22806355_2.fastq.gz | Fastqsanger.gz | |||
| SRR22806356_1.fastq.gz | Fastqsanger.gz |
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Project description:A de novo mutation in ITPR3 causes severe combined 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.
2024-06-18 | PXD038284 | Pride
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.
2023-01-02 | E-MTAB-12432 | biostudies-arrayexpress
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.
2023-07-05 | E-MTAB-13124 | biostudies-arrayexpress
Project description:An IRF4 de novo mutation affecting the DNA binding domain of encoded IRF4 protein (mutDBD) was identified in a patient presenting with combined immunodeficiency. The patient exhibited profound susceptibility to opportunistic infections notably Pneumocystis jirovecii and humoral immunodeficiency caused by a failure of terminal B cell differentiation. A heterozygous IRF4 missense variant resulting in a phenylalanine-to-leucine replacement within the interferon activation domain of the encoded IRF4 protein (mutIAD) was identified in three patients from a multigenerational family suffering from a novel autosomal dominant disease predominantly presenting as a hypogammaglobulinemia with recurrent infections. In this experiment we aimed to investigate the effect of the two different mutations on IRF4 genomic binding.
2023-03-06 | GSE199684 | GEO
Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patientâs defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors. 3 samples were analyzed in duplicate, Sample 1 was human HSC transduced with GFP only lentivirus which served as controls, Sample 2 was human HSC transduced with lentivirus expressing FLAG-tagged WT BCL11B and GFP, Sample 3 was human HSC transduced with lentivirus expressing FLAG-tagged mutant BCL11B and GFP
2016-07-29 | E-GEOD-84941 | biostudies-arrayexpress
Project description:An IRF4 de novo mutation affecting the DNA binding domain of encoded IRF4 protein (mutDBD) was identified in a patient presenting with combined immunodeficiency. The patient exhibited profound susceptibility to opportunistic infections notably Pneumocystis jirovecii and humoral immunodeficiency caused by a failure of terminal B cell differentiation. A heterozygous IRF4 missense variant resulting in a phenylalanine-to-leucine replacement within the interferon activation domain of the encoded IRF4 protein (mutIAD) was identified in three patients from a multigenerational family suffering from a novel autosomal dominant disease predominantly presenting as a hypogammaglobulinemia with recurrent infections. In these experiments we aimed to investigate the effect of the two different mutations on IRF4 genomic binding and regulated transcription. This SuperSeries is composed of the SubSeries listed below.
2023-03-06 | GSE199686 | GEO
Project description:An IRF4 de novo mutation affecting the DNA binding domain of encoded IRF4 protein (mutDBD) was identified in a patient presenting with combined immunodeficiency. The patient exhibited profound susceptibility to opportunistic infections notably Pneumocystis jirovecii and humoral immunodeficiency caused by a failure of terminal B cell differentiation. A heterozygous IRF4 missense variant resulting in a phenylalanine-to-leucine replacement within the interferon activation domain of the encoded IRF4 protein (mutIAD) was identified in three patients from a multigenerational family suffering from a novel autosomal dominant disease predominantly presenting as a hypogammaglobulinemia with recurrent infections. In this experiment we aimed to investigate the effect of the two different mutations on IRF4 regulated transcription.
2023-03-06 | GSE199685 | GEO