IRF4 haploinsufficiency in a family with Whipple’s disease
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PROVIDER: PRJNA415625 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:IRF4 Haploinsufficiency Impairs Affinity Maturation
| PRJNA767888 | ENA
Project description:Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.
| S-EPMC5915175 | biostudies-literature
Project description:Whipple's disease (WD) affects only a very small minority of individuals infected by Tropheryma whipplei (Tw). Asymptomatic and chronic carriage of the causative organism is less rare and therefore, the pathogenesis of WD is poorly understood. Here we studied transcriptome responses in peripheral blood mononuclear cells (PBMCs) that were obtained from members of a large multiplex French kindred including otherwise healthy WD patients, healthy chronic carriers of Tw and other unrealted control subjects.
2017-10-30 | GSE102862 | GEO
Project description:Single cell RNA seq (scRNA-seq) has emerged as a powerful tool to determine the composition of heterogeneous cell states in a tissue. We found that Irf4+/- antigen specific B cells were functionally impaired in affinity maturation. The goal of this study was to determine whether Irf4+/- antigen specific B cells exhibited distinct cellular composition compared to wild type cells. Sequence data from 8360 cells revealed a similar distribution and numbers of cell states between cells of Irf4+/- or Irf4+/+ genotypes.
2021-10-04 | GSE185188 | GEO
Project description:Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4-/- T cells and IRF4 binding was diminished in Batf-/- T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription. Genome-wide transcription factors mapping and binding of IRF4, BATF, IRF8, STAT3, JUN etc in WT, Irf4-/- and Batf-/- mice in different cell types (B cells, CD4+ T cells and TH17 cells) cultured with or without IL-21 was conducted. RNA-Seq is conducted in mouse B cells, CD4+ T cells, TH1/TH2/TH9/TH17/Treg.
2012-09-18 | E-GEOD-39756 | biostudies-arrayexpress
Project description:A heterozygous IRF4 missense variant located 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 this IRF4 mutation on the transcriptome of T lymphocytes.
2023-03-06 | GSE214888 | 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 genomic binding.
2023-03-06 | GSE199684 | 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 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:Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4-/- T cells and IRF4 binding was diminished in Batf-/- T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.
2012-09-18 | GSE39756 | GEO
Project description:Disease modelling of core pre-mRNA splicing factor haploinsufficiency
| PRJNA532422 | ENA