Beate Hagl, Benedikt D. Spielberger, Betina Neumann, Simon J. Pelham, Dharmendra Pandey, Andreas Schlundt, Camille Barro, Anica Lechner, Christine Wolf, Elissa K. Deenick, Michael Sattler, Stuart G. Tangye, Simon Rothenfusser, Ellen D. Renner
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引用次数: 0
Abstract
STAT3-hyper-IgE syndrome (STAT3-HIES) is an inborn error of immunity caused by heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3). In this study, we evaluate the functional relevance of a previously undescribed heterozygous STAT3 variant in a patient with clinical findings of STAT3-HIES. Flow cytometry, quantitative real-time PCR, pull-down assays, native PAGE, DNA-binding ELISA, and 3D-structural data analysis were performed. Genetic analysis identified the heterozygous STAT3 variant NM_139276.2:c.2127G>C (NP_644805.1:p.(K709N); short: p.K709N) in a patient with a clinical and laboratory phenotype characteristic of STAT3-HIES, including early onset severe eczema, chronic lung disease, eosinophilia, and elevated serum IgE levels. While STAT3 p.K709N did not significantly affect STAT3 phosphorylation, STAT3 target gene expression was impaired in patient cells. Expression of STAT3 p.K709N and wild-type STAT3 in STAT3-deficient cells indicated a dominant-negative effect by the mutation. Analysis of 3D-structural data and modeling suggested a central role of the affected amino acid K709 in stabilizing a C-terminal loop in STAT3 essential for dimer formation. Consequently, p.K709N resulted in diminished STAT3 dimerization and reduced DNA binding in patient cells. Functional analyses verified STAT3 p.K709N to cause STAT3-HIES and suggest that STAT3 p.K709N impairs STAT3 dimer formation.
期刊介绍:
The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.