作者
L Wang,Dominik Aschenbrenner,Zhuotong Zeng,Xu Cao,Doris Mayr,Minesh Mehta,Melania Capitani,Neil Warner,Jieyi Pan,Q Li,Tiancheng Zuo,Sarit Cohen-Kedar,Jijun Lu,Rico Chandra Ardy,Daniel J. Mulder,Dilan Dissanayake,Kun Peng,Zhenglan Huang,X Li,Y Wang,X Wang,S Li,Samuel J. Bullers,Anís N. Gammage,Klaus Warnatz,Schiefer A-I.,Gergely Kriván,Vera Goda,Wha Kahr,Mathieu Lemaire,Lu Cy,Iram Siddiqui,Michael G. Surette,Daniel Kotlarz,Karin R. Engelhardt,Helen Griffin,Robert Rottapel,Hélène Decaluwe,R. M. Laxer,Michele Proietti,Sophie Hambleton,Suzanne Elcombe,Guo C-H.,Bodo Grimbacher,Iris Dotan,S C Ng,Spencer A. Freeman,Scott B. Snapper,Claudius Klein,Kaan Boztug,Yi-Chung Huang,D Li,Holm H. Uhlig,Aleixo M. Muise
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.