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

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

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
04 2021
Historique:
received: 25 04 2020
accepted: 27 01 2021
pubmed: 31 3 2021
medline: 21 4 2021
entrez: 30 3 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41588-021-00803-4 PMID: 33782605 PMC: PMC8245161
pubmed: 33782605
doi: 10.1038/s41588-021-00803-4
pii: 10.1038/s41588-021-00803-4
pmc: PMC8245161
mid: NIHMS1667689
doi:

Substances chimiques

Protein Kinase Inhibitors 0
SYK protein, human EC 2.7.10.2
Syk Kinase EC 2.7.10.2

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

500-510

Subventions

Organisme : Wellcome Trust
ID : 207556_Z_17_Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 207556/Z/17/Z
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : RC2 DK118640
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034854
Pays : United States
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : RC2 DK122532
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom

Investigateurs

Helen R Griffin (HR)
Sophie Hambleton (S)

Commentaires et corrections

Type : CommentIn
Type : ErratumIn

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Auteurs

Lin Wang (L)

Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.
SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
ORCID: 0000-0002-1530-6542

Dominik Aschenbrenner (D)

Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.
ORCID: 0000-0001-7580-2567

Zhiyang Zeng (Z)

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.

Xiya Cao (X)

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.

Daniel Mayr (D)

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

Meera Mehta (M)

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Melania Capitani (M)

Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.

Neil Warner (N)

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
ORCID: 0000-0002-9207-5979

Jie Pan (J)

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Liren Wang (L)

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.
School of Life Sciences, East China Normal University, Shanghai, China.

Qi Li (Q)

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Tao Zuo (T)

Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.
Institute of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.

Sarit Cohen-Kedar (S)

Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.

Jiawei Lu (J)

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai, China.
School of Life Sciences, East China Normal University, Shanghai, China.

Rico Chandra Ardy (RC)

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

Daniel J Mulder (DJ)

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
ORCID: 0000-0003-2974-855X

Dilan Dissanayake (D)

Division of Rheumatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

Kaiyue Peng (K)

Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.

Zhiheng Huang (Z)

Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.

Xiaoqin Li (X)

Department of Gastroenterology, Zhengzhou Children's Hospital, Zhengzhou, China.

Yuesheng Wang (Y)

Department of Gastroenterology, Zhengzhou Children's Hospital, Zhengzhou, China.

Xiaobing Wang (X)

Neonate Department, Sanmenxia Central Hospital, Sanmenxia, China.

Shuchao Li (S)

Department of Pediatrics, Lushi County Renmin Hospital, Sanmenxia, China.

Samuel Bullers (S)

Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

Anís N Gammage (AN)

Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
ORCID: 0000-0002-7493-8988

Klaus Warnatz (K)

Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Freiburg, Germany.

Ana-Iris Schiefer (AI)

Department of Clinical Pathology, Medical University Vienna, Vienna, Austria.

Gergely Krivan (G)

National Institute of Hematology and Infectious Diseases, Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest, Budapest, Hungary.

Vera Goda (V)

National 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 Kahr (WHA)

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Division of Haematology/Oncology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
ORCID: 0000-0002-2832-7158

Mathieu Lemaire (M)

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Nephrology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

Chien-Yi Lu (CY)

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Iram Siddiqui (I)

Division of Pathology, Department of Pediatric Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.

Michael G Surette (MG)

Department of Medicine, Farncombe Family Digestion Health Institute, McMaster University, Hamilton, Ontario, Canada.
ORCID: 0000-0003-0086-4995

Daniel Kotlarz (D)

Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.

Karin R Engelhardt (KR)

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Helen R Griffin (HR)

Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Robert Rottapel (R)

Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Division of Rheumatology, St. Michael's Hospital, Toronto, Ontario, Canada.

Hélène Decaluwe (H)

Division of Immunology and Rheumatology, Department of Pediatrics, Sainte-Justine University Hospital, Montreal, Quebec, Canada.
Cytokine and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Université de Montréal, Montreal, Quebec, Canada.

Ronald M Laxer (RM)

Division of Rheumatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Michele Proietti (M)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.

Sophie Hambleton (S)

Faculty of Medical Sciences, 100KGP England, Newcastle University, Newcastle upon Tyne, UK.
ORCID: 0000-0001-7954-3267

Suzanne Elcombe (S)

Department of Immunology, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Cong-Hui Guo (CH)

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Bodo Grimbacher (B)

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
DZIF - German Center for Infection Research, Satellite Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.

Iris Dotan (I)

Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Siew C Ng (SC)

Center for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, China.
Institute of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
ORCID: 0000-0002-6850-4454

Spencer A Freeman (SA)

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

Scott B Snapper (SB)

Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
ORCID: 0000-0003-0267-4247

Christoph Klein (C)

Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig Maximilian University Munich, Munich, Germany.
ORCID: 0000-0003-0956-0445

Kaan Boztug (K)

Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Ying Huang (Y)

Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China. yhuang815@163.com.
ORCID: 0000-0002-4931-4006

Dali Li (D)

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: 0000-0002-0046-8493

Holm H Uhlig (HH)

Translational Gastroenterology Unit and Biomedical Research Centre, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford, Oxford, UK.
Department of Pediatrics, John Radcliffe Hospital, Oxford, UK.

Aleixo M Muise (AM)

SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. aleixo.muise@utoronto.ca.
ORCID: 0000-0001-9624-3346

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