ArticleNature genetics2021
Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.
Erratum issuedOpen access · greenAbstract read
In one paragraph
Article in Nature genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 57 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
57citing papers in PubMed, 1 pooled it
6.2field-weighted citation impact, top 2% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 100 citations in OpenAlex.
- Large-scale GWAS meta-analysis of serum antibody levels in healthy individuals reveals distinct genetic architectures.Genes and immunity · 2026Pooled it
- Human CD21Journal of human immunity · 2026Review
- Targeting SYK to alleviate MDSC-driven immunosuppression and augment anti-PD1 efficacy.Science China. Life sciences · 2026Article
- BIRC3 (Encoding cIAP2) Variants Result in Dysregulated RIPK1 Signaling Leading to Increased Epithelial Cell Death and Are Associated With Monogenic Crohn's Disease.Gastroenterology · 2026Article
- Non-receptor tyrosine kinase signaling pathways and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- Molecular Insights into Oral Manifestations in Sjögren's Disease.International journal of molecular sciences · 2026Review
- Syk inhibition limits autoimmunity and abnormal B cell phenotype and function in mice with B cell-specific TRAF3 deficiency.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- ANGPTL2 inhibits macrophage pyroptosis and alleviates rheumatoid arthritis progression by regulating mitophagy via IGFBP5.Cell death & disease · 2026Article
- Construction of pathogenic Sec16a mutation mouse model using CRISPR/Cas9.Animal models and experimental medicine · 2026Article
- Porphyromonas gingivalis-derived extracellular vesicles aggravate bone destruction in rheumatoid arthritis by promoting Syk-dependent osteoclastogenesis.International journal of oral science · 2026Article
- Video capsule endoscopy in very early onset inflammatory bowel disease: a multicenter retrospective study from the Chinese Pediatric VCE Study Group.Translational gastroenterology and hepatology · 2026Article
- Article
- SYK Activation Enhances Dendritic Cell Functions in Spontaneous Rheumatoid Arthritis.Inflammation · 2025Article
- Uncovering the molecular basis of kinase activity and substrate recognition with phospho-PCA.bioRxiv : the preprint server for biology · 2025Article
- Integrated transcriptomic and phenotypic analysis reveals tissue-specific regulatory effects of guanidinoacetic acid in cattle.BMC genomics · 2025Article
- Phosphorylation at Y317 on Syk negatively regulates both ITAM- and hemITAM-mediated signaling and function in platelets.Blood advances · 2025Article
- Novel SYK Variant Causes Enhanced SYK Autophosphorylation and PI3K Activation in an Antibody-Deficient Patient.Journal of clinical immunology · 2025Article
- Genomic Insights into the Origin, High Fecundity and Environmental Adaptation of Hu Sheep.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Intravenous immunoglobulin ameliorates doxorubicin-induced intestinal mucositis by inhibiting the Syk/PI3K/Akt axis and ferroptosis.Apoptosis : an international journal on programmed cell death · 2025Article
- Article
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
56 authors at 20 institutions in 9 countries.
Lin Wang *Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.ORCID http://orcid.org/0000-0002-1530-6542
Dominik Aschenbrenner *Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-7580-2567
Zhiyang Zeng *Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Xiya CaoShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Daniel MayrLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Meera MehtaSickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Melania CapitaniTranslational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Neil WarnerSickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-9207-5979
Jie PanSickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Liren WangShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.
Qi LiSickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Tao ZuoCenter for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.
Sarit Cohen-KedarFelsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Jiawei LuShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.
Rico Chandra ArdyLudwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Daniel J MulderSickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0003-2974-855X
Dilan DissanayakeDivision of Rheumatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Kaiyue PengDepartment of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.
Zhiheng HuangDepartment of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.
Xiaoqin LiDepartment of Gastroenterology, Zhengzhou Children's Hospital, Zhengzhou, China.
Yuesheng WangDepartment of Gastroenterology, Zhengzhou Children's Hospital, Zhengzhou, China.
Xiaobing WangNeonate Department, Sanmenxia Central Hospital, Sanmenxia, China.
Shuchao LiDepartment of Pediatrics, Lushi County Renmin Hospital, Sanmenxia, China.
Samuel BullersTranslational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Anís N GammageTranslational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-7493-8988
Klaus WarnatzDepartment of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Ana-Iris SchieferDepartment of Clinical Pathology, Medical University Vienna, Vienna, Austria.
Gergely KrivanNational Institute of Hematology and Infectious Diseases, Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest, Budapest, Hungary.
Vera GodaNational Institute of Hematology and Infectious Diseases, Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest, Budapest, Hungary.
Walter H A KahrDepartment of Biochemistry, University of Toronto, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-2832-7158
Mathieu LemaireDepartment of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Genomics England Research Consortium
Chien-Yi LuDepartment of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Iram SiddiquiDivision of Pathology, Department of Pediatric Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.
Michael G SuretteDepartment of Medicine, Farncombe Family Digestion Health Institute, McMaster University, Hamilton, Ontario, Canada.ORCID http://orcid.org/0000-0003-0086-4995
Daniel KotlarzDepartment of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
Karin R EngelhardtTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Helen R GriffinTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Robert RottapelPrincess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Hélène DecaluweDivision of Immunology and Rheumatology, Department of Pediatrics, Sainte-Justine University Hospital, Montreal, Quebec, Canada.
Ronald M LaxerDivision of Rheumatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Michele ProiettiInstitute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
Sophie HambletonFaculty of Medical Sciences, 100KGP England, Newcastle University, Newcastle upon Tyne, UK.ORCID http://orcid.org/0000-0001-7954-3267
Suzanne ElcombeDepartment of Immunology, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Cong-Hui GuoSickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Bodo GrimbacherInstitute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
Iris DotanDivision of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.
Siew C NgCenter for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.ORCID http://orcid.org/0000-0002-6850-4454
Spencer A FreemanDepartment of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Scott B SnapperDivision of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0267-4247
Christoph KleinDepartment of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.ORCID http://orcid.org/0000-0003-0956-0445
Kaan Boztug *Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
Ying Huang *Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China. yhuang815@163.com.ORCID http://orcid.org/0000-0002-4931-4006
Dali Li *Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. dlli@bio.ecnu.edu.cn.ORCID http://orcid.org/0000-0002-0046-8493
Holm H Uhlig *Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Aleixo M Muise *SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.ORCID http://orcid.org/0000-0001-9624-3346
University of Toronto · CANewcastle University · GBEast China Normal University · CNSickKids Foundation · CAAustrian Academy of Sciences · ATChildren's Hospital of Fudan University · CNJohn Radcliffe Hospital · GBUniversity of Freiburg · DEChinese University of Hong Kong · HKLudwig-Maximilians-Universität München · DENational Center for Epidemiology · HUNuffield Orthopaedic Centre · GBTel Aviv University · ILZhengzhou Children's Hospital · CNBrigham and Women's Hospital · USCentre Hospitalier Universitaire Sainte-Justine · CAHospital for Sick Children · CAMcMaster University · CAMedical University of Vienna · ATOntario Institute for Cancer Research · CA
Funding
STRUCTURE-FUNCTION RELATIONSHIPS IN THE ALIMENTARY TRACTP30DK034854 · NIDDK · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JONATHAN C KAGAN · 1986 to 2026
$32.4MCOngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepositoryRC2DK118640 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI James Richard Goldenring, Izumi Kaji · 2019 to 2026
$14.8MIdentifying Immune and Epithelial Network Signatures in Very Early Onset Inflammatory Bowel DiseaseRC2DK122532 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI KLEIN, CHRISTOPH, MUISE, ALEIXO M · 2020 to 2024
$9.1MCancer Research UKDepartment of HealthMedical Research CouncilNIDDK NIH HHS P30 DK034854NIDDK NIH HHS RC2 DK118640NIDDK NIH HHS RC2 DK122532Wellcome Trust 207556/Z/17/ZWellcome Trust 207556_Z_17_Z
Abstract
Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
Indexed as
AdultAnimalsArthritisBase SequenceBone Marrow TransplantationColitisDermatitisFamilyFemaleGene ExpressionGene Knock-In TechniquesHumansInfantLymphoma, Large B-Cell, DiffuseMaleMiceProtein Kinase InhibitorsSyk KinaseSYK protein, human
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.