@article{3270eb15d591441f83f0821554d5716e,
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 Freeman, {Spencer A.}",
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 = "אנגלית",
volume = "53",
pages = "500--510",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",
}
