{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T07:09:38Z","timestamp":1793171378230,"version":"4.5.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006196","name":"University of Oulu","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Clin Immunol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains, can be loss- or gain-of-function (LOF and GOF).\n                    <jats:italic>STAT3<\/jats:italic>\n                    N-terminal domain (NTD) mutations are rare, and their biological effects remain incompletely understood. We explored the significance of\n                    <jats:italic>STAT3<\/jats:italic>\n                    NTD p.Trp37* variant in a patient with chronic pulmonary aspergillosis and a low Hyper-IgE syndrome (HIES) score. In cell culture models, the expression of full-length p.Trp37* allele showed shorter STAT3 protein expression suggesting a re-initiation (Met99 or Met143). STAT3 activity using luciferase reporter assay showed a twofold-increased activity of the STAT3 p.Trp37* STAT3 protein compared with WT STAT3 at basal level and upon IL-6 stimulation. In contrast, the activity of the short pTrp37* peptide (amino acids 1 to 37) was amorphic but without dominant negative (DN) effect on transcriptional activity or STAT3 Tyr705 phosphorylation. The proteins initiated at Met99 and Met143 were surprisingly hypermorphic. In carriers\u2019 peripheral blood mononuclear cells (PBMCs), both WT and mutated STAT3 mRNA were equally present and the global amount of STAT3 protein was not significantly reduced. In stimulated heterozygous carriers\u2019 PBMCs, however, STAT3 Tyr705 phosphorylation and Th17 were reduced but not completely abolished. This suggests a DN effect of an unknown product of the p.Trp37* allele. Transcriptomics analysis of PBMCs from the index revealed selectively distinct gene expression. We conclude that heterozygosity for the NTD p.Trp37*\n                    <jats:italic>STAT3<\/jats:italic>\n                    mutation defines a novel allelic form of STAT3 deficiency, associated with a chronic pulmonary aspergillosis and minor signs of HIES.\n                  <\/jats:p>","DOI":"10.1007\/s10875-025-01867-1","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T09:46:19Z","timestamp":1739180779000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pulmonary Aspergillosis and Low HIES Score in a Family with STAT3 N-Terminal Domain Mutation"],"prefix":"10.1007","volume":"45","author":[{"given":"Suiane","family":"Lima de Souza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaki","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virpi","family":"Glumoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salla","family":"Keskitalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keela","family":"Pikkarainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timi","family":"Martelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meri","family":"Kaustio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Saarela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Kuismin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Lappi-Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Airi","family":"Jartti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Yannopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Tiitto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko R. J.","family":"Sepp\u00e4nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Boisson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Laurent","family":"Casanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markku","family":"Varjosalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Hautala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4658-7463","authenticated-orcid":false,"given":"Zhi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"1867_CR1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1097\/MOH.0000000000000206","volume":"23","author":"LR Forbes","year":"2016","unstructured":"Forbes LR, Milner J, Haddad E. Signal transducer and activator of transcription 3: a year in review. Curr Opin Hematol. 2016;23:23\u20137. https:\/\/doi.org\/10.1097\/MOH.0000000000000206.","journal-title":"Curr Opin Hematol"},{"key":"1867_CR2","doi-asserted-by":"publisher","unstructured":"Asano T, Khourieh J, Zhang P, Rapaport F, Spaan AN, Li J, et al. Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance. Journal of Experimental Medicine 2021;218. https:\/\/doi.org\/10.1084\/jem.20202592.","DOI":"10.1084\/jem.20202592"},{"key":"1867_CR3","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.jaci.2009.10.059","volume":"125","author":"C Woellner","year":"2010","unstructured":"Woellner C, Gertz EM, Sch\u00e4ffer AA, Lagos M, Perro M, Glocker E-O, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. Journal of Allergy and Clinical Immunology. 2010;125:424-432.e8. https:\/\/doi.org\/10.1016\/j.jaci.2009.10.059.","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"1867_CR4","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1007\/s10875-021-01051-1","volume":"41","author":"C Tsilifis","year":"2021","unstructured":"Tsilifis C, Freeman AF, Gennery AR. STAT3 Hyper-IgE Syndrome\u2014an Update and Unanswered Questions. J Clin Immunol. 2021;41:864\u201380. https:\/\/doi.org\/10.1007\/s10875-021-01051-1.","journal-title":"J Clin Immunol"},{"key":"1867_CR5","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1186\/ar4069","volume":"14","author":"PF Yong","year":"2012","unstructured":"Yong PF, Freeman AF, Engelhardt KR, Holland S, Puck JM, Grimbacher B. An update on the hyper-IgE syndromes. Arthritis Res Ther. 2012;14:228. https:\/\/doi.org\/10.1186\/ar4069.","journal-title":"Arthritis Res Ther"},{"key":"1867_CR6","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/ng.3040","volume":"46","author":"SE Flanagan","year":"2014","unstructured":"Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46:812\u20134. https:\/\/doi.org\/10.1038\/ng.3040.","journal-title":"Nat Genet"},{"key":"1867_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.09.002","author":"JW Leiding","year":"2022","unstructured":"Leiding JW, Vogel TP, Santarlas VGJ, Mhaskar R, Smith MR, Carisey A, et al. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome. Journal of Allergy and Clinical Immunology. 2022. https:\/\/doi.org\/10.1016\/j.jaci.2022.09.002.","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"1867_CR8","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1016\/j.jaci.2019.06.003","volume":"144","author":"H G\u00f6\u00f6s","year":"2019","unstructured":"G\u00f6\u00f6s H, Fogarty CL, Sahu B, Plagnol V, Rajam\u00e4ki K, Nurmi K, et al. Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy. Journal of Allergy and Clinical Immunology. 2019;144:1364\u201376. https:\/\/doi.org\/10.1016\/j.jaci.2019.06.003.","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"1867_CR9","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1016\/j.jaci.2022.06.007","volume":"150","author":"L Lodi","year":"2022","unstructured":"Lodi L, Faletti LE, Maccari ME, Consonni F, Gro\u00df M, Pagnini I, et al. STAT3-confusion-of-function: Beyond the loss and gain dualism. Journal of Allergy and Clinical Immunology. 2022;150:1237-1241.e3. https:\/\/doi.org\/10.1016\/j.jaci.2022.06.007.","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"1867_CR10","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1016\/j.jaci.2018.05.009","volume":"142","author":"M Natarajan","year":"2018","unstructured":"Natarajan M, Hsu AP, Weinreich MA, Zhang Y, Niemela JE, Butman JA, et al. Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency. Journal of Allergy and Clinical Immunology. 2018;142:993-997.e3. https:\/\/doi.org\/10.1016\/j.jaci.2018.05.009.","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"1867_CR11","doi-asserted-by":"publisher","unstructured":"Hsu AP, Korzeniowska A, Aguilar CC, Gu J, Karlins E, Oler AJ, et al. Immunogenetics associated with severe coccidioidomycosis. JCI Insight 2022;7. https:\/\/doi.org\/10.1172\/jci.insight.159491.","DOI":"10.1172\/jci.insight.159491"},{"key":"1867_CR12","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/1478-811X-11-83","volume":"11","author":"A Mohr","year":"2013","unstructured":"Mohr A, Fahrenkamp D, Rinis N, M\u00fcller-Newen G. Dominant-negative activity of the STAT3-Y705F mutant depends on the N-terminal domain. Cell Communication and Signaling. 2013;11:83. https:\/\/doi.org\/10.1186\/1478-811X-11-83.","journal-title":"Cell Communication and Signaling"},{"key":"1867_CR13","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1242\/jcs.072520","volume":"124","author":"M Vogt","year":"2011","unstructured":"Vogt M, Domoszlai T, Kleshchanok D, Lehmann S, Schmitt A, Poli V, et al. The role of the N-terminal domain in dimerization and nucleocytoplasmic shuttling of latent STAT3. J Cell Sci. 2011;124:900\u20139. https:\/\/doi.org\/10.1242\/jcs.072520.","journal-title":"J Cell Sci"},{"key":"1867_CR14","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.jaci.2020.12.656","volume":"148","author":"M Kaustio","year":"2021","unstructured":"Kaustio M, Nayebzadeh N, Hinttala R, Tapiainen T, \u00c5str\u00f6m P, Mamia K, et al. Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction. Journal of Allergy and Clinical Immunology. 2021;148:599\u2013611. https:\/\/doi.org\/10.1016\/j.jaci.2020.12.656.","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"1867_CR15","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","volume":"176","author":"K Jaganathan","year":"2019","unstructured":"Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, et al. Predicting Splicing from Primary Sequence with Deep Learning. Cell. 2019;176:535-548.e24. https:\/\/doi.org\/10.1016\/j.cell.2018.12.015.","journal-title":"Cell"},{"key":"1867_CR16","doi-asserted-by":"publisher","first-page":"4005","DOI":"10.1073\/pnas.88.9.4005","volume":"88","author":"AJ Buckler","year":"1991","unstructured":"Buckler AJ, Chang DD, Graw SL, Brook JD, Haber DA, Sharp PA, et al. Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc Natl Acad Sci. 1991;88:4005\u20139. https:\/\/doi.org\/10.1073\/pnas.88.9.4005.","journal-title":"Proc Natl Acad Sci"},{"key":"1867_CR17","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/0378-1119(95)00223-S","volume":"161","author":"TC Burn","year":"1995","unstructured":"Burn TC, Connors TD, Klinger KW, Landes GM. Increased exon-trapping efficiency through modifications to the pSPL3 splicing vector. Gene. 1995;161:183\u20137. https:\/\/doi.org\/10.1016\/0378-1119(95)00223-S.","journal-title":"Gene"},{"key":"1867_CR18","doi-asserted-by":"publisher","unstructured":"Keskitalo S, Haapaniemi E, Einarsdottir E, Rajam\u00e4ki K, Heikkil\u00e4 H, Ilander M, et al. Novel TMEM173 Mutation and the Role of Disease Modifying Alleles. Frontiers in Immunology 2019;10. https:\/\/doi.org\/10.3389\/fimmu.2019.02770.","DOI":"10.3389\/fimmu.2019.02770"},{"key":"1867_CR19","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1101\/gr.7.10.986","volume":"7","author":"S Audic","year":"1997","unstructured":"Audic S, Claverie J-M. The Significance of Digital Gene Expression Profiles. Genome Res. 1997;7:986\u201395. https:\/\/doi.org\/10.1101\/gr.7.10.986.","journal-title":"Genome Res"},{"key":"1867_CR20","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1038\/s41467-018-03523-2","volume":"9","author":"X Liu","year":"2018","unstructured":"Liu X, Salokas K, Tamene F, Jiu Y, Weldatsadik RG, \u00d6hman T, et al. An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nat Commun. 2018;9:1188. https:\/\/doi.org\/10.1038\/s41467-018-03523-2.","journal-title":"Nat Commun"},{"key":"1867_CR21","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1111\/cas.13525","volume":"109","author":"N Shahmarvand","year":"2018","unstructured":"Shahmarvand N, Nagy A, Shahryari J, Ohgami RS. Mutations in the signal transducer and activator of transcription family of genes in cancer. Cancer Sci. 2018;109:926\u201333. https:\/\/doi.org\/10.1111\/cas.13525.","journal-title":"Cancer Sci"},{"key":"1867_CR22","doi-asserted-by":"publisher","unstructured":"Selenius JS, Martelius T, Pikkarainen S, Siitonen S, Mattila E, Pietik\u00e4inen R, et al. Unexpectedly High Prevalence of Common Variable Immunodeficiency in Finland. Frontiers in Immunology 2017;8. https:\/\/doi.org\/10.3389\/fimmu.2017.01190.","DOI":"10.3389\/fimmu.2017.01190"},{"key":"1867_CR23","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1158\/2326-6066.CIR-15-0014","volume":"3","author":"C Yue","year":"2015","unstructured":"Yue C, Shen S, Deng J, Priceman SJ, Li W, Huang A, et al. STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3\/CXCL10 Axis. Cancer Immunol Res. 2015;3:864\u201370. https:\/\/doi.org\/10.1158\/2326-6066.CIR-15-0014.","journal-title":"Cancer Immunol Res"},{"key":"1867_CR24","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.immuni.2017.05.005","volume":"46","author":"S Iwata","year":"2017","unstructured":"Iwata S, Mikami Y, Sun H-W, Brooks SR, Jankovic D, Hirahara K, et al. The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells. Immunity. 2017;46:983-991.e4. https:\/\/doi.org\/10.1016\/j.immuni.2017.05.005.","journal-title":"Immunity"},{"key":"1867_CR25","doi-asserted-by":"publisher","unstructured":"Powell MD, Read KA, Sreekumar BK, Oestreich KJ. Ikaros Zinc Finger Transcription Factors: Regulators of Cytokine Signaling Pathways and CD4+ T Helper Cell Differentiation. Frontiers in Immunology 2019;10. https:\/\/doi.org\/10.3389\/fimmu.2019.01299.","DOI":"10.3389\/fimmu.2019.01299"},{"key":"1867_CR26","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1183\/09031936.00054810","volume":"37","author":"NL Smith","year":"2011","unstructured":"Smith NL, Denning DW. Underlying conditions in chronic pulmonary aspergillosis including simple aspergilloma. Eur Respir J. 2011;37:865. https:\/\/doi.org\/10.1183\/09031936.00054810.","journal-title":"Eur Respir J"},{"key":"1867_CR27","doi-asserted-by":"publisher","unstructured":"Zaragoza R, Sole-Violan J, Cusack R, Rodriguez A, Reyes LF, Martin-Loeches I. Invasive Pulmonary Aspergillosis: Not Only a Disease Affecting Immunosuppressed Patients. Diagnostics 2023;13. https:\/\/doi.org\/10.3390\/diagnostics13030440.","DOI":"10.3390\/diagnostics13030440"},{"key":"1867_CR28","doi-asserted-by":"publisher","first-page":"3284","DOI":"10.1128\/MCB.00060-15","volume":"35","author":"T Hu","year":"2015","unstructured":"Hu T, Yeh JE, Pinello L, Jacob J, Chakravarthy S, Yuan G-C, et al. Impact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity. Mol Cell Biol. 2015;35:3284\u2013300. https:\/\/doi.org\/10.1128\/MCB.00060-15.","journal-title":"Mol Cell Biol"}],"container-title":["Journal of Clinical Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-025-01867-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10875-025-01867-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10875-025-01867-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T15:46:00Z","timestamp":1777304760000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10875-025-01867-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,10]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["1867"],"URL":"https:\/\/doi.org\/10.1007\/s10875-025-01867-1","relation":{},"ISSN":["0271-9142","1573-2592"],"issn-type":[{"value":"0271-9142","type":"print"},{"value":"1573-2592","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,10]]},"assertion":[{"value":"11 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 January 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by Ethics Committee of Oulu University Hospital.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent for participation was obtained from all individuals.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Consent for publication was obtained from all individuals.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare that they have no conflict of interest.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of Interest"}}],"article-number":"73"}}