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Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens Homo

PROVIDER: GSE215406 | GEO | 2023/02/20

REPOSITORIES: GEO

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Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Project description:We descrie a cohort of 10 families, with 16 patients, that presented with severe early onset allergic disease since birth. Disease inhertance was in an autosomal dominant manner and heterozygous variants in STAT6 were identified in all patients. Whole blood bulk RNAsequencing was done on patient 6 to understand treatment specific transcriptomic changes in this patient.

2023-02-20 | GSE222646 | GEO

Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease [scRNAseq]

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Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease [bulk_RNAseq]

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Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Project description:Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

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Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

Project description:Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease

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Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease [scRNAseq]

Project description:Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease [scRNAseq]

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Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease [bulk_RNAseq]

Project description:Human Germline Heterozygous Gain-of-Function STAT6 Variants Cause Severe Allergic Disease [bulk_RNAseq]

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Heterozygous <i>OAS1</i> gain-of-function variants cause an autoinflammatory immunodeficiency.

Project description:Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

| S-EPMC8392508 | biostudies-literature

Heterozygous OAS1 Gain-of-Function Variants Cause a Polymorphic Autoinflammatory and Immunodeficiency Syndrome

Project description:Oligoadenylate synthase 1 (OAS1) is a type-1 interferon-inducible, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate (2-5A) to activate RNaseL as a means of antiviral defense. We report four de novo heterozygous OAS1 variants in five patients. Variant OAS1 proteins show dsRNA-independent gain-of-function 2-5A synthetase activity that results in RNaseL-mediated RNA-cleavage, transcriptomic downregulation, and functional impairment and/or apoptosis of monocytes, iPSC-derived macrophages, and B-cells. This leads to a polymorphic syndrome of monocyte, macrophage, and B-cell deficiency characterized by autoinflammation, pulmonary alveolar proteinosis, and hypogammaglobulinemia. RNase-L-inhibition in vitro mitigates, and hematopoietic cell transplantation in vivo corrects the autoinflammatory and immunodeficiency phenotype.

2021-06-18 | GSE173667 | GEO

Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma.

Project description:The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.245 words.

| S-EPMC10499697 | biostudies-literature

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