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

Genomics England Research Consortium

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)500-510
Number of pages11
JournalNature Genetics
Volume53
Issue number4
DOIs
StatePublished - Apr 2021

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