Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.
Wang L., Aschenbrenner D., Zeng Z., Cao X., Mayr D., Mehta M., Capitani M., Warner N., Pan J., Wang L., Li Q., Zuo T., Cohen-Kedar S., Lu J., Ardy RC., Mulder DJ., Dissanayake D., Peng K., Huang Z., Li X., Wang Y., Wang X., Li S., Bullers S., Gammage AN., Warnatz K., Schiefer A-I., Krivan G., Goda V., Kahr WHA., Lemaire M., Genomics England Research Consortium None., Lu C-Y., Siddiqui I., Surette MG., Kotlarz D., Engelhardt KR., Griffin HR., Rottapel R., Decaluwe H., Laxer RM., Proietti M., Hambleton S., Elcombe S., Guo C-H., Grimbacher B., Dotan I., Ng SC., Freeman SA., Snapper SB., Klein C., Boztug K., Huang Y., Li D., Uhlig HH., Muise AM.
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.