Yaoyuan Zhang, Rhiannon Morris, Grant J Brown, Ayla May D Lorenzo, Xiangpeng Meng, Nadia J Kershaw, Pamudika Kiridena, Gaétan Burgio, Simon Gross, Jean Y Cappello, Qian Shen, Hao Wang, Cynthia Turnbull, Tom Lea-Henry, Maurice Stanley, Zhijia Yu, Fiona D Ballard, Aaron Chuah, James C Lee, Ann-Maree Hatch, Anselm Enders, Seth L Masters, Alexander P Headley, Peter Trnka, Dominic Mallon, Jeffery T Fletcher, Giles D Walters, Mario Šestan, Marija Jelušić, Matthew C Cook, Vicki Athanasopoulos, David A Fulcher, Jeffrey J Babon, Carola G Vinuesa, Julia I Ellyard
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1...
April 1, 2024: Journal of Experimental Medicine