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

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

Nature genetics (2021-03-31)

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, 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

PMID33782605

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.