Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

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dc.contributor.authorBeziat, Vivien
dc.contributor.authorTavernier, Simon J.
dc.contributor.authorChen, Yin-Huai
dc.contributor.authorMa, Cindy S.
dc.contributor.authorMaterna, Marie
dc.contributor.authorLaurence, Arian
dc.contributor.authorStaal, Jens
dc.date.accessioned2024-02-23T14:20:46Z
dc.date.available2024-02-23T14:20:46Z
dc.date.issued2020
dc.departmentNEÜen_US
dc.description.abstractAutosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.en_US
dc.description.sponsorshipSt. Giles Foundation; Rockefeller University; Institut National de la Sante et de la Recherche Medicale; Paris Descartes University; Howard Hughes Medical Institute; Job Research Foundation; French National Research Agency under the Investissement d'avenir program [ANR-10-IAHU-01]; GENMSMD project [ANR-16-CE17-0005-01]; LTh-MSMD-CMCD project [ANR-18-CE93-0008-01]; PNEUMOPID project [ANR 14-CE15-0009-01]; HGDIFD project [ANR-14-CE15-0006-01]; French Foundation for Medical Research [EQU201903007798]; Jeffrey Model Foundation; Yale Center for Mendelian Genomics - National Human Genome Research Institute [UM1HG006504]; National Heart, Lung, and Blood Institute; GSP Coordinating Center [U24 HG008956]; NIH [R01AI127564, R01AI128976]; National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program [UL1 TR001866]; University Hospital Ghent Spearhead Initiative for Immunology Research; Grand Challenges Program of VIB; Flemish Government [VR 2016 2312 Doc.1521/4]; Deutsche Forschungsgemeinschaft [SFB1160/2_B5, CIBSS - EXC-2189, 390939984, RESIST - EXC 2155, 39087428]; European Joint Programme on Rare Diseases of the European Union [GR1617/14-1/iPAD]; Bundesministerium fur Bildung und Forschung [GAIN_ 01GM1910A]; university research grant (BOF-University Ghent); French National Research Agency [NKIRP-ANR-13-PDOC-0025-01]; National Health and Medical Research Council of Australia; Biomedical Research Centre BRC Oxford; Celgene; NIH Common Fund through the Office of Strategic Coordination/Office of the NIH [U01HG007709]en_US
dc.description.sponsorshipThis work was supported by the St. Giles Foundation; the Rockefeller University; Institut National de la Sante et de la Recherche Medicale; Paris Descartes University; the Howard Hughes Medical Institute; the Job Research Foundation; the French National Research Agency under the Investissement d'avenir program (grant number ANR-10-IAHU-01), the GENMSMD project (grant ANR-16-CE17-0005-01 to L.-J. Couderc), the LTh-MSMD-CMCD project (grant ANR-18-CE93-0008-01), the PNEUMOPID project (grant ANR 14-CE15-0009-01), and the HGDIFD project (grant ANR-14-CE15-0006-01); the French Foundation for Medical Research (EQU201903007798); the Jeffrey Model Foundation; the Yale Center for Mendelian Genomics (UM1HG006504) funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute; the GSP Coordinating Center (U24 HG008956), which contributed to cross-program scientific initiatives and provided logistical and general study coordination; the NIH (grant R01AI127564); the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program (UL1 TR001866); the University Hospital Ghent Spearhead Initiative for Immunology Research; and the Grand Challenges Program of VIB. This VIB program received support from the FlemishGovernmentunder the Management Agreement 2017-2021 (VR 2016 2312 Doc.1521/4). T.A. Chatila is supported by NIH grant R01AI128976. B. Grimbacher is funded by the Deutsche Forschungsgemeinschaft: SFB1160/2_B5, under Germany's Excellence Strategy (CIBSS - EXC-2189 - Project ID 390939984; and RESIST - EXC 2155 - Project ID 39087428); through the European Joint Programme on Rare Diseases of the European Union, managed by Deutsche Forschungsgemeinschaft (grant GR1617/14-1/iPAD); and through the Bundesministerium fur Bildung und Forschung (grant GAIN_ 01GM1910A). S.J. Tavernier is a postdoctoral fellow with the Fund for Scientific Research Flanders (FWO 1236920N). M.R.L. Maglorius Renkilaraj and J. Rosain are supported by Institut National de la Sante et de la Recherche Medicale. F. Haerynck was funded by a university research grant (BOF-University Ghent). V. B ' eziatwas supported by the French National Research Agency (grant NKIRP-ANR-13-PDOC-0025-01). S.G. Tangye is supported by the National Health and Medical Research Council of Australia and the Job Research Foundation. H.H. Uhlig is supported by the Biomedical Research Centre BRC Oxford. H.H. Uhlig, A. Laurence, and Y.-H. Chen are supported by Celgene. The research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH director under award U01HG007709. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.en_US
dc.identifier.doi10.1084/jem.20191804
dc.identifier.issn0022-1007
dc.identifier.issn1540-9538
dc.identifier.issue6en_US
dc.identifier.pmid32207811en_US
dc.identifier.scopus2-s2.0-85082275467en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1084/jem.20191804
dc.identifier.urihttps://hdl.handle.net/20.500.12452/13299
dc.identifier.volume217en_US
dc.identifier.wosWOS:000538138000012en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherRockefeller Univ Pressen_US
dc.relation.ispartofJournal Of Experimental Medicineen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleDominant-negative mutations in human IL6ST underlie hyper-IgE syndromeen_US
dc.typeArticleen_US

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