TY - JOUR TI - Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice 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 - 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 - Freeman, Spencer A. AU - Snapper, Scott B. AU - Klein, Christoph AU - Boztug, Kaan AU - Huang, Ying AU - Li, Dali AU - Uhlig, Holm H. AU - Muise, Aleixo M. T2 - Nature Genetics 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. DA - 2021/03/29/ PY - 2021 DO - 10.1038/s41588-021-00803-4 DP - www.nature.com SP - 1 EP - 11 LA - en SN - 1546-1718 UR - https://www.nature.com/articles/s41588-021-00803-4 Y2 - 2021/03/29/18:03:22 ER -