Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus
Mahmoud Al‐Azab, Elina Idiiatullina, Ziyang Liu, Meng Lin, Katja Hrovat-Schaale, Huifang Xian, Jianheng Zhu, Mandy Yang, Bingtai Lu, Zhiyao Zhao, Yiyi Liu, Jingjie Chang, Xiaotian Li, Caiqin Guo, Yunfeng Liu, Qi Wu, Jiazhang Chen, Chaoting Lan, Ping Zeng, Jun Cui, Xia Gao, Wenhao Zhou, Yan Zhang, Yuxia Zhang, Seth L. Masters, Yuxia Zhang, Seth L. Masters
Abstract
Abstract Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1 V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.