{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:37:24Z","timestamp":1760060244675,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the NIH","award":["RS-2024-00411137","RS-2024-00440614"],"award-info":[{"award-number":["RS-2024-00411137","RS-2024-00440614"]}]},{"name":"National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","award":["RS-2024-00411137","RS-2024-00440614"],"award-info":[{"award-number":["RS-2024-00411137","RS-2024-00440614"]}]},{"name":"Intramural Research Programs (IRPs) of National Heart, Lung, and Blood Institute (NHLBI)","award":["RS-2024-00411137","RS-2024-00440614"],"award-info":[{"award-number":["RS-2024-00411137","RS-2024-00440614"]}]},{"name":"National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT)","award":["RS-2024-00411137","RS-2024-00440614"],"award-info":[{"award-number":["RS-2024-00411137","RS-2024-00440614"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>STAT3 mutations are commonly observed in human pathology yet have no uniform patient presentation. Their effects range from cancer and autoimmunity to primary immunodeficiencies and bone deformity. Designing animal models of those mutations can help researchers identify their direct effects to better inform the clinical setting. In this manuscript, we report a mouse model harboring the same mutation as an autosomal-dominant hyper-IgE syndrome (AD-HIES) patient reported in the literature. Surprisingly, while the deletion of five amino acids in the SH2 domain of STAT3 did result in frequency changes in several immune populations as measured by complete blood count and flow cytometry analysis, it did not yield the expected phenotype of AD-HIES, with no increase in serum IgE or eosinophil count. We additionally provide structural analysis of the STAT3G656_M660del deletion, visualizing changes in protein architecture and potential effects on the neighboring Y705 phosphorylation site. Our model showcases the sexually dimorphic immune dysregulation caused by a STAT3 mutation and highlights that predicted gain- and loss-of-function mutations can yield unexpected phenotypes.<\/jats:p>","DOI":"10.3390\/ijms26167675","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T11:41:53Z","timestamp":1754653313000},"page":"7675","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mouse Model of STAT3 Mutation Resulting in Job\u2019s Syndrome Diverges from Human Pathology"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1661-079X","authenticated-orcid":false,"given":"Jakub","family":"Jankowski","sequence":"first","affiliation":[{"name":"Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1038-471X","authenticated-orcid":false,"given":"Jichun","family":"Chen","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6785-616X","authenticated-orcid":false,"given":"Gyuhyeok","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung-Gwon","family":"Lee","sequence":"additional","affiliation":[{"name":"Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neal","family":"Young","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5213-9299","authenticated-orcid":false,"given":"Jungwook","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8319-9841","authenticated-orcid":false,"given":"Lothar","family":"Hennighausen","sequence":"additional","affiliation":[{"name":"Section of Genetics and Physiology, Laboratory of Cellular and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2016.05.001","article-title":"STAT3 signaling in immunity","volume":"31","author":"Hillmer","year":"2016","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s12943-020-01258-7","article-title":"Targeting STAT3 in Cancer Immunotherapy","volume":"19","author":"Zou","year":"2020","journal-title":"Mol. 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