Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

作者：Mahmoud Al‐Azab, Elina Idiiatullina, Meng Lin, Katja Hrovat-Schaale, Huifang Xian, Jianheng Zhu, Mandy Yang, Bingtai Lu, Ziyang Liu, Zhiyao Zhao, Yiyi Liu, Jingjie Chang, Xiaotian Li, Caiqin Guo, Ping Zeng, Jun Cui, Xia Gao, Yan Zhang, Yan Zhang, Yuxia Zhang, Yuxia Zhang, Seth L. Masters · 发表于：medRxiv · 年份：2023 · DOI：10.1101/2023.10.15.23296507 · 被引用次数：8 · 研究领域：Systemic Lupus Erythematosus Research、Immune Response and Inflammation、Cytokine Signaling Pathways and Interactions

Abstract Rare genetic variants in TLR7 are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localisation into endosomes, however it has only been genetically linked to lupus in mice and dogs. We now identify a novel variant in UNC93B1 (T314A) located proximally to the TLR7 transmembrane domain, in a patient with childhood-onset systemic lupus erythematosus (SLE). Further examination in a cohort of East Asian patients revealed seven who encode UNC93B1 (V117L), which is a rare but highly significant risk factor for this disease, when compared to the corresponding general population. The variant is associated with increased expression of type I IFNs and NF-kB cytokines in patients plasma and PBMC. This was confirmed using cell line models, with exaggerated responses to stimulation of TLR7/8, but not TLR3 or TLR9, and the process can be inhibited by targeting the TLR signaling molecules IRAK1/4. For UNC93B1 (V117L) we then created the orthologous mutation in mice (V138L), which results in a spontaneous lupus-like disease in heterozygotes, that is 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 SLE. One sentence summary Rare genetic variants in UNC93B1 predispose to childhood-onset lupus via TLR7-IRAK1/4, validated with a corresponding mouse model.