2. Academic Validation
  3. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice

  • Nat Genet. 2021 Apr;53(4):500-510. doi: 10.1038/s41588-021-00803-4.
Lin Wang # 1 2,  Dominik Aschenbrenner # 3 4,  Zhiyang Zeng # 5,  Xiya Cao 5,  Daniel Mayr 6 7 8,  Meera Mehta 2 9,  Melania Capitani 3 4,  Neil Warner 2,  Jie Pan 2 9,  Liren Wang 10 11,  Qi Li 2 9,  Tao Zuo 12 13,  Sarit Cohen-Kedar 14 15,  Jiawei Lu 10 11,  Rico Chandra Ardy 6 7 8,  Daniel J Mulder 2,  Dilan Dissanayake 16,  Kaiyue Peng 1,  Zhiheng Huang 1,  Xiaoqin Li 17,  Yuesheng Wang 17,  Xiaobing Wang 18,  Shuchao Li 19,  Samuel Bullers 3 4 20,  Anís N Gammage 3 20,  Klaus Warnatz 21 22,  Ana-Iris Schiefer 23,  Gergely Krivan 24,  Vera Goda 24,  Walter H A Kahr 9 25 26,  Mathieu Lemaire 9 26 27,  Genomics England Research Consortium,  Chien-Yi Lu 9,  Iram Siddiqui 28,  Michael G Surette 29,  Daniel Kotlarz 30,  Karin R Engelhardt 31,  Helen R Griffin 31,  Robert Rottapel 32 33 34,  Hélène Decaluwe 35 36,  Ronald M Laxer 16 37,  Michele Proietti 38,  Sophie Hambleton 39,  Suzanne Elcombe 40,  Cong-Hui Guo 2 9,  Bodo Grimbacher 38 41 42 43,  Iris Dotan 15 44,  Siew C Ng 12 13,  Spencer A Freeman 9 26,  Scott B Snapper 45 46 47,  Christoph Klein 30,  Kaan Boztug # 6 7 8 48,  Ying Huang # 49,  Dali Li # 50,  Holm H Uhlig # 3 4,  Aleixo M Muise # 51 52 53 54 55
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.
  • 2 SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 3 Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
  • 4 Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.
  • 5 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
  • 6 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
  • 7 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 8 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
  • 9 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
  • 10 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.
  • 11 School of Life Sciences, East China Normal University, Shanghai, China.
  • 12 Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.
  • 13 Institute of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
  • 14 Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 15 Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.
  • 16 Division of Rheumatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 17 Department of Gastroenterology, Zhengzhou Children's Hospital, Zhengzhou, China.
  • 18 Neonate Department, Sanmenxia Central Hospital, Sanmenxia, China.
  • 19 Department of Pediatrics, Lushi County Renmin Hospital, Sanmenxia, China.
  • 20 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
  • 21 Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 22 Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Freiburg, Germany.
  • 23 Department of Clinical Pathology, Medical University Vienna, Vienna, Austria.
  • 24 National Institute of Hematology and Infectious Diseases, Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest, Budapest, Hungary.
  • 25 Division of Haematology/Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 26 Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 27 Division of Nephrology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
  • 28 Division of Pathology, Department of Pediatric Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 29 Department of Medicine, Farncombe Family Digestion Health Institute, McMaster University, Hamilton, Ontario, Canada.
  • 30 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
  • 31 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
  • 32 Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 33 Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • 34 Division of Rheumatology, St. Michael's Hospital, Toronto, Ontario, Canada.
  • 35 Division of Immunology and Rheumatology, Department of Pediatrics, Sainte-Justine University Hospital, Montreal, Quebec, Canada.
  • 36 Cytokine and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Université de Montréal, Montreal, Quebec, Canada.
  • 37 Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 38 Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  • 39 Faculty of Medical Sciences, 100KGP England, Newcastle University, Newcastle upon Tyne, UK.
  • 40 Department of Immunology, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 41 DZIF - German Center for Infection Research, Satellite Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  • 42 CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  • 43 RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
  • 44 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 45 Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
  • 46 Harvard Medical School, Boston, MA, USA.
  • 47 Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
  • 48 St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
  • 49 Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China. [email protected].
  • 50 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. [email protected].
  • 51 SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. [email protected].
  • 52 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 53 Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. [email protected].
  • 54 Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 55 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • # Contributed equally.
PMID: 33782605 DOI: 10.1038/s41588-021-00803-4
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.

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