Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children's Hospital of Fudan University, Shanghai, China.
SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
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.
脾酪氨酸激酶（SYK）是一种关键的免疫信号分子和治疗靶点。我们在六位患有免疫缺陷、多器官炎症性疾病（如结肠炎、关节炎和皮炎）和弥漫性大 B 细胞淋巴瘤的患者中发现了具有破坏性的单等位基因 SYK 变异体。这些 SYK 变异体增加了磷酸化并增强了下游信号，表明具有功能获得。患者变异体（p.Ser550Tyr）的 SYK-Ser544Tyr 敲入（knock-in）小鼠模型再现了人类疾病的某些方面，这些方面可以部分通过 SYK 抑制剂或从野生型小鼠移植骨髓来治疗。我们的研究表明，SYK 功能获得性变异体导致一种潜在可治疗的炎症性疾病。
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