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
  • 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.