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

Wang, Lin; Aschenbrenner, Dominik; Zeng, Zhiyang; Cao, Xiya; Mayr, Daniel; Mehta, Meera; Capitani, Melania; Warner, Neil; Pan, Jie; Wang, Liren; Li, Qi; Zuo, Tao; Cohen-Kedar, Sarit; Lu, Jiawei; Ardy, Rico Chandra; Mulder, Daniel J.; Dissanayake, Dilan; Peng, Kaiyue; Huang, Zhiheng; Li, Xiaoqin; Wang, Yuesheng; Wang, Xiaobing; Li, Shuchao; Bullers, Samuel; Gammage, Anis N.; Warnatz, Klaus; Schiefer, Ana-Iris; Krivan, Gergely; Goda, Vera; Kahr, Walter H. A.; Lemaire, Mathieu; Lu, Chien-Yi; Siddiqui, Iram; Surette, Michael G.; Kotlarz, Daniel; Engelhardt, Karin R.; Griffin, Helen R.; Rottapel, Robert; Decaluwe, Helene; Laxer, Ronald M.; Proietti, Michele; Hambleton, Sophie; Elcombe, Suzanne; Guo, Cong-Hui; Grimbacher, Bodo; Dotan, Iris; Ng, Siew C.; Freeman, Spencer A.; Snapper, Scott B.; Klein, Christoph; Boztug, Kaan; Huang, Ying; Li, Dali; Uhlig, Holm H. and Muise, Aleixo M. (2021): Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. In: Nature Genetics, Vol. 53, No. 4: pp. 500-510

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. Individuals with SYK gain-of-function variants develop immunodeficiency and systemic inflammation, which are recapitulated in a knock-in mouse model. Treatment of these mice with bone marrow transplantation or with a SYK inhibitor ameliorates disease symptoms, highlighting potential therapeutic strategies for patients with SYK mutations.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1061-4036
• Language: English