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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.

SUBMITTER: Wang L 

PROVIDER: S-EPMC8245161 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Wang Lin L   Aschenbrenner Dominik D   Zeng Zhiyang Z   Cao Xiya X   Mayr Daniel D   Mehta Meera M   Capitani Melania M   Warner Neil N   Pan Jie J   Wang Liren L   Li Qi Q   Zuo Tao T   Cohen-Kedar Sarit S   Lu Jiawei J   Ardy Rico Chandra RC   Mulder Daniel J DJ   Dissanayake Dilan D   Peng Kaiyue K   Huang Zhiheng Z   Li Xiaoqin X   Wang Yuesheng Y   Wang Xiaobing X   Li Shuchao S   Bullers Samuel S   Gammage Anís N AN   Warnatz Klaus K   Schiefer Ana-Iris AI   Krivan Gergely G   Goda Vera V   Kahr Walter H A WHA   Lemaire Mathieu M   Lu Chien-Yi CY   Siddiqui Iram I   Surette Michael G MG   Kotlarz Daniel D   Engelhardt Karin R KR   Griffin Helen R HR   Rottapel Robert R   Decaluwe Hélène H   Laxer Ronald M RM   Proietti Michele M   Hambleton Sophie S   Elcombe Suzanne S   Guo Cong-Hui CH   Grimbacher Bodo B   Dotan Iris I   Ng Siew C SC   Freeman Spencer A SA   Snapper Scott B SB   Klein Christoph C   Boztug Kaan K   Huang Ying Y   Li Dali D   Uhlig Holm H HH   Muise Aleixo M AM  

Nature genetics 20210329 4

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 t  ...[more]

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