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

Genomics England Research Consortium

doi:10.1038/s41588-021-00803-4

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

Genomics England Research Consortium

生命科学学院

Children's Hospital of Fudan University
University of Toronto
University of Oxford
John Radcliffe Hospital
East China Normal University
Ludwig Boltzmann Institute
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Children's Cancer Research Institute
Chinese University of Hong Kong
Tel Aviv University
Rabin Medical Center Israel
Zhengzhou Children’s Hospital
Sanmenxia Central Hospital
Lushi County Renmin Hospital
University of Freiburg
Medical University of Vienna
Central Hospital of Southern Pest
Newcastle University
McMaster University
Ludwig Maximilian University of Munich
University of Toronto
Sainte-Justine University Hospital
Newcastle upon Tyne Hospitals NHS Foundation Trust
Boston Children's Hospital
Harvard University
Brigham and Women’s Hospital

科研成果: 期刊稿件 › 文章 › 同行评审

90 引用（Scopus）

摘要

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.

源语言	英语
页（从-至）	500-510
页数	11
期刊	Nature Genetics
卷	53
期	4
DOI	https://doi.org/10.1038/s41588-021-00803-4
出版状态	已出版 - 4月 2021

联合国可持续发展目标

此成果有助于实现下列可持续发展目标：

可持续发展目标 3 良好健康与福祉

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10.1038/s41588-021-00803-4

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@article{fee5b3dd598845eeb172ced50f8a4085,

title = "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice",

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.",

author = "\{Genomics England Research Consortium\} and Lin Wang and Dominik Aschenbrenner and Zhiyang Zeng and Xiya Cao and Daniel Mayr and Meera Mehta and Melania Capitani and Neil Warner and Jie Pan and Liren Wang and Qi Li and Tao Zuo and Sarit Cohen-Kedar and Jiawei Lu and Ardy, \{Rico Chandra\} and Mulder, \{Daniel J.\} and Dilan Dissanayake and Kaiyue Peng and Zhiheng Huang and Xiaoqin Li and Yuesheng Wang and Xiaobing Wang and Shuchao Li and Samuel Bullers and Gammage, \{An{\'i}s N.\} and Klaus Warnatz and Schiefer, \{Ana Iris\} and Gergely Krivan and Vera Goda and Kahr, \{Walter H.A.\} and Mathieu Lemaire and Griffin, \{Helen R.\} and Sophie Hambleton and Lu, \{Chien Yi\} and Iram Siddiqui and Surette, \{Michael G.\} and Daniel Kotlarz and Engelhardt, \{Karin R.\} and Griffin, \{Helen R.\} and Robert Rottapel and H{\'e}l{\`e}ne Decaluwe and Laxer, \{Ronald M.\} and Michele Proietti and Sophie Hambleton and Suzanne Elcombe and Guo, \{Cong Hui\} and Bodo Grimbacher and Iris Dotan and Ng, \{Siew C.\} and Dali Li",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = apr,

doi = "10.1038/s41588-021-00803-4",

language = "英语",

volume = "53",

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journal = "Nature Genetics",

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TY - JOUR

T1 - Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice

AU - Genomics England Research Consortium

AU - Wang, Lin

AU - Aschenbrenner, Dominik

AU - Zeng, Zhiyang

AU - Cao, Xiya

AU - Mayr, Daniel

AU - Mehta, Meera

AU - Capitani, Melania

AU - Warner, Neil

AU - Pan, Jie

AU - Wang, Liren

AU - Li, Qi

AU - Zuo, Tao

AU - Cohen-Kedar, Sarit

AU - Lu, Jiawei

AU - Ardy, Rico Chandra

AU - Mulder, Daniel J.

AU - Dissanayake, Dilan

AU - Peng, Kaiyue

AU - Huang, Zhiheng

AU - Li, Xiaoqin

AU - Wang, Yuesheng

AU - Wang, Xiaobing

AU - Li, Shuchao

AU - Bullers, Samuel

AU - Gammage, Anís N.

AU - Warnatz, Klaus

AU - Schiefer, Ana Iris

AU - Krivan, Gergely

AU - Goda, Vera

AU - Kahr, Walter H.A.

AU - Lemaire, Mathieu

AU - Griffin, Helen R.

AU - Hambleton, Sophie

AU - Lu, Chien Yi

AU - Siddiqui, Iram

AU - Surette, Michael G.

AU - Kotlarz, Daniel

AU - Engelhardt, Karin R.

AU - Griffin, Helen R.

AU - Rottapel, Robert

AU - Decaluwe, Hélène

AU - Laxer, Ronald M.

AU - Proietti, Michele

AU - Hambleton, Sophie

AU - Elcombe, Suzanne

AU - Guo, Cong Hui

AU - Grimbacher, Bodo

AU - Dotan, Iris

AU - Ng, Siew C.

AU - Li, Dali

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85103424041

U2 - 10.1038/s41588-021-00803-4

DO - 10.1038/s41588-021-00803-4

M3 - 文章

C2 - 33782605

AN - SCOPUS:85103424041

SN - 1061-4036

VL - 53

SP - 500

EP - 510

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

摘要

联合国可持续发展目标

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