Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice Academic Article uri icon

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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.

authors

  • 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, Anís N
  • Warnatz, Klaus
  • Schiefer, Ana-Iris
  • Krivan, Gergely
  • Goda, Vera
  • Kahr, Walter HA
  • Lemaire, Mathieu
  • Griffin, Helen R
  • Hambleton, Sophie
  • Lu, Chien-Yi
  • Siddiqui, Iram
  • Surette, Michael
  • Kotlarz, Daniel
  • Engelhardt, Karin R
  • Griffin, Helen R
  • Rottapel, Robert
  • Decaluwe, Hélène
  • 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
  • Muise, Aleixo M

publication date

  • April 2021

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