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Human ZNF341 deficiency underlies a recessive form of hyper IgE syndrome by disrupting STAT3 transcription-dependent STAT3 activity

ABSTRACT: Heterozygosity for human STAT3 dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-IgE syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including, most notably the STAT3 promoter. The patients’ cells have low basal levels of STAT3 mRNA and protein. The auto-induction of STAT3 production, activation, and function by STAT3-activating cytokines is particularly strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack Th17 cells, have an excess of Th2 cells, and low memory B cells, due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341-dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent auto-induction and sustained activity of STAT3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113945 | GEO | 2018/06/04

REPOSITORIES: GEO

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A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

Project description:Heterozygosity for human STAT3 dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-IgE syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including, most notably the STAT3 promoter. The patients’ cells have low basal levels of STAT3 mRNA and protein. The auto-induction of STAT3 production, activation, and function by STAT3-activating cytokines is particularly strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack Th17 cells, have an excess of Th2 cells, and low memory B cells, due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341-dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent auto-induction and sustained activity of STAT3.

2018-05-30 | GSE113194 | GEO

ZNF341 controls STAT3 expression and thereby immunocompetence

Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindred. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

2018-05-02 | GSE107719 | GEO

Genome-wide transcriptome analysis in PBMCs of HIES patient A.II.1 compared to healthy sibling A.II.5

Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

2018-05-04 | GSE109030 | GEO

Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance

Project description:Here we describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341.

2021-06-12 | GSE153886 | GEO

A mouse model of HIES reveals pro and anti-inflammatory functions of STAT3

Project description:Mutations of STAT3 underlie the autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in non-hematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Thus, predicting the efficacy of HSCT for HIES is difficult. To begin to dissect the importance of STAT3 in hematopoietic and non-hematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of HIES. The effect of IL-6 and IL-10 on BM-DC gene expression was investigated in cell derived from wild type or mut-Stat3 mice

2014-03-06 | E-GEOD-55607 | biostudies-arrayexpress

A mouse model of HIES reveals pro and anti-inflammatory functions of STAT3

2014-03-06 | GSE55607 | GEO

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Project description:Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hy- per IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in re- cipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous pa- tients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when over- expressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phos- phorylation, DNA binding, and transcriptional activity. In immor- talized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding muta- tions, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequenc- ing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

2020-04-30 | GSE149602 | GEO

STAT3 regulates osteogenesis, making it critical for skeletal development and bone homeostasis

Project description:Skeletal deformities are typical clinical manifestations of autosomal dominant hyper-immunoglobulin E syndrome (AD-HIES), but the treatment is still limited. AD-HIES is mainly caused by dominant-negative mutations in signal transducer and activator of transcription 3 (STAT3). Clarifying the mechanisms by which STAT3 inactivation destructs bone metabolism is, therefore, important. Although, a few lines of data indicate osteoporosis induced by STAT3 inactivation may be related to increased osteoclast activity, here, we firstly report that deletion of Stat3 in osteoblasts, but not in osteoclasts, induced AD-HIES-like bone defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture in mice, and these defects were resulted from impaired osteogenesis induced by STAT3 inactivation in osteoblasts, but not increased osteoclast activity. Mechanistic analysis revealed a novel regulatory model in which STAT3 drove osteoblast differentiation via promoting distal-less homeobox 5 transcription in cooperation with MSX1. Furthermore, inducible deletion of Stat3 in osteoblasts also inhibited osteogenesis and induced bone loss in adult mice. Meaningfully, pharmacological inhibition of STAT3 induced bone loss, while activation of STAT3 partially prevent bone loss due to tail sus-pension. Taken together, STAT3 is critical for both modulating skeletal development and maintaining bone homeostasis, and inactivation of STAT3 in osteoblasts, but not in osteoclasts, induced AD-HIES-related skeletal deformities by impairing osteogenesis, providing new insights for their treatment.

2021-07-28 | GSE173711 | GEO

Identification of IL-21-induced STAT3 dependent genes in human B cells

Project description:IL-21 induces B cell activation, and differentiation into antibody-secreting plasmablasts in vitro. This process is abolished by loss-of function mutations in STAT3 We used microarrays to identify genes that are induced by IL-21 in a STAT3-dependent manner Sort-purified naÃ¯ve B cells from four healthy donors and three patients with AD-HIES due to heterozygous STAT3 mutations were cultured for four days with CD40L in the presence or absence of IL-21 (50ng/ml). After four days, RNA was extracted from the harvested cells and the genetic profile was analysed by microarray.

2014-01-09 | E-GEOD-51587 | biostudies-arrayexpress

Next Generation Sequencing Facilitates Quantitative Analysis of mRNA expression of STAT3 deficiency skin

Project description:Dominant-negative mutations of signal transducer and activator of transcription 3 (STAT3) signaling which controls epithelial proliferation in various tissues, leads to atopic dermatitis (AD) in hyper IgE syndrome (HIES). We found that the STAT3 signaling in keratinocytes is required to maintain skin homeostasis through this transcriptome analysis.

2021-10-15 | GSE185585 | GEO

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