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

Lin Wang; Dominik Aschenbrenner; Zhiyang Zeng; Xiya Cao; Daniel Mayr; Meera Mehta; Melania Capitani; Neil Warner; Jie Pan; Liren Wang; Qi Li; Tao Zuo; Sarit Cohen-Kedar; Jiawei Lu; Rico Chandra Ardy; Daniel J Mulder; Dilan Dissanayake; Kaiyue Peng; Zhiheng Huang; Xiaoqin Li; Yuesheng Wang; Xiaobing Wang; Shuchao Li; Samuel Bullers; Anís N Gammage; Klaus Warnatz; Ana-Iris Schiefer; Gergely Krivan; Vera Goda; Walter H A Kahr; Mathieu Lemaire; Genomics England Research Consortium; Chien-Yi Lu; Iram Siddiqui; Michael G Surette; Daniel Kotlarz; Karin R Engelhardt; Helen R Griffin; Robert Rottapel; Hélène Decaluwe; Ronald M Laxer; Michele Proietti; Sophie Hambleton; Suzanne Elcombe; Cong-Hui Guo; Bodo Grimbacher; Iris Dotan; Siew C Ng; Spencer A Freeman; Scott B Snapper; Christoph Klein; Kaan Boztug; Ying Huang; Dali Li; Holm H Uhlig; Aleixo M Muise

doi:10.1038/s41588-021-00803-4

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. Epub 2021 Mar 29.

Authors

Lin Wang^#^{1

2}, Dominik Aschenbrenner^#^{3

4}, Zhiyang Zeng^#⁵, Xiya Cao⁵, Daniel Mayr^{6

7

8}, Meera Mehta^{2

9}, Melania Capitani^{3

4}, Neil Warner², 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 Mulder², Dilan Dissanayake¹⁶, Kaiyue Peng¹, Zhiheng Huang¹, Xiaoqin Li¹⁷, Yuesheng Wang¹⁷, Xiaobing Wang¹⁸, Shuchao Li¹⁹, Samuel Bullers^{3

4

20}, Anís N Gammage^{3

20}, Klaus Warnatz^{21

22}, Ana-Iris Schiefer²³, Gergely Krivan²⁴, Vera Goda²⁴, Walter H A Kahr^{9

25

26}, Mathieu Lemaire^{9

26

27}; Genomics England Research Consortium; Chien-Yi Lu⁹, Iram Siddiqui²⁸, Michael G Surette²⁹, Daniel Kotlarz³⁰, Karin R Engelhardt³¹, Helen R Griffin³¹, Robert Rottapel^{32

33

34}, Hélène Decaluwe^{35

36}, Ronald M Laxer^{16

37}, Michele Proietti³⁸, Sophie Hambleton³⁹, Suzanne Elcombe⁴⁰, 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 Klein³⁰, 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}

Collaborators

Genomics England Research Consortium:
Helen R Griffin, Sophie Hambleton

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. yhuang815@163.com.
⁵⁰ 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.
⁵¹ SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
⁵² Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
⁵³ Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
⁵⁴ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
⁵⁵ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Arthritis / genetics*
Arthritis / immunology
Arthritis / pathology
Arthritis / therapy
Base Sequence
Bone Marrow Transplantation
Colitis / genetics*
Colitis / immunology
Colitis / pathology
Colitis / therapy
Dermatitis / genetics*
Dermatitis / immunology
Dermatitis / pathology
Dermatitis / therapy
Family
Female
Gene Expression
Gene Knock-In Techniques
Humans
Infant
Lymphoma, Large B-Cell, Diffuse / genetics*
Lymphoma, Large B-Cell, Diffuse / immunology
Lymphoma, Large B-Cell, Diffuse / pathology
Lymphoma, Large B-Cell, Diffuse / therapy
Male
Mice
Mice, Knockout
Middle Aged
Mutation
Pedigree
Protein Kinase Inhibitors / pharmacology
Syk Kinase / antagonists & inhibitors
Syk Kinase / deficiency
Syk Kinase / genetics*

Substances

Protein Kinase Inhibitors
SYK protein, human
Syk Kinase

Abstract

Publication types

MeSH terms

Substances

Grants and funding