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

Nat Genet. 2021 Apr;53(4):500-510. doi: 10.1038/s41588-021-00803-4. Epub 2021 Mar 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural