Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation
| العنوان: | Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation |
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| المؤلفون: | Tala Shahin, Daniel Mayr, Mohamed R. Shoeb, Hye Sun Kuehn, Birgit Hoeger, Sarah Giuliani, Lisa M. Gawriyski, Özlem Yüce Petronczki, Jérôme Hadjadj, Sevgi Köstel Bal, Samaneh Zoghi, Matthias Haimel, Raul Jimenez Heredia, David Boutboul, Michael P. Triebwasser, Fanny Rialland-Battisti, Nathalie Costedoat Chalumeau, Pierre Quartier, Stuart G. Tangye, Thomas A. Fleisher, Nima Rezaei, Neil Romberg, Sylvain Latour, Markku Varjosalo, Florian Halbritter, Frédéric Rieux-Laucat, Irinka Castanon, Sergio D. Rosenzweig, Kaan Boztug |
| المساهمون: | Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, Biosciences, Molecular Systems Biology |
| المصدر: | Blood Advances |
| مصطلحات موضوعية: | EXPRESSION, Proteomics, Ikaros Transcription Factor, Germ Cells, HELIOS, T-CELLS, IKAROS, 1182 Biochemistry, cell and molecular biology, Humans, Hematology, T-Lymphocytes, Regulatory, Germ-Line Mutation |
| الوصف: | Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation. |
| اللغة: | English |
| تدمد: | 2473-9537 2473-9529 |
| DOI: | 10.1182/bloodadvances.2021006367 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7ff9a9e511974f360284e94491365b91Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7ff9a9e511974f360284e94491365b91 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 24739537 24739529 |
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| DOI: | 10.1182/bloodadvances.2021006367 |