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We identified a novel heterozygous germline mutation\n                    <jats:italic>STAT6<\/jats:italic>\n                    c.1255G\u2009&gt;\u2009C, 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 (\n                    <jats:italic>XBP1<\/jats:italic>\n                    and\n                    <jats:italic>EPAS1<\/jats:italic>\n                    ) 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.\n                  <\/jats:p>\n                  <jats:p>245 words.<\/jats:p>","DOI":"10.1007\/s10875-023-01530-7","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T18:01:25Z","timestamp":1686765685000},"page":"1611-1622","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with 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Informed consent for obtaining blood and skin biopsy samples for functional assays were taken in accordance with the Declaration of Helsinki and with approvals from local ethics committees with ethical approval (reference numbers 04\/Q0501\/119 and 06\/Q0508\/16).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"All participants provided written informed consent prior to participation.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"SOB has received grant support from CSL Behring and personal fees or travel expenses from Immunodeficiency Canada\/IAACI, CSL Behring, Baxalta US Inc and Biotest. ECM has received honoraria from GlaxoSmithKline, AstraZeneca and Orchard Therapeutics. BG was an advisor to the following companies: UCB Pharma S.A., Epimune GmbH, Octapharma, Atheneum Partners GmbH, and GigaGen Inc. and a speaker for Janssen-Cilag GmbH. The rest of the authors declare that they have no conflicts of interest.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}