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

Al-Azab, M; Idiiatullina, E; LIU, Z; Lin, M; Hrovat-Schaale, K; Xian, H; Zhu, J; Yang, M; Lu, B; Zhao, Z; Liu, Y; Chang, J; Li, X; Guo, C; Liu, Y; Wu, Q; Chen, J; Lan, C; Zeng, P; Cui, J; Gao, X; Zhou, W; Zhang, Y; Zhang, Y; Masters, SL

Author(s): Al-Azab, M; Idiiatullina, E; LIU, Z; Lin, M; Hrovat-Schaale, K; Xian, H; Zhu, J; Yang, M; Lu, B; Zhao, Z; Liu, Y; Chang, J; Li, X; Guo, C; Liu, Y; Wu, Q; Chen, J; Lan, C; Zeng, P; Cui, J; Gao, X; Zhou, W; Zhang, Y; Zhang, Y; Masters, SL;
Details: Publication Year 2024-06,Volume 25,Issue #6,Page 969-980
Journal Title: Nature Immunology
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.
Publisher: Springer Nature
Keywords: *Lupus Erythematosus, Systemic/genetics; Humans; Animals; *Toll-Like Receptor 7/genetics/metabolism; *Genetic Predisposition to Disease; Mice; Child; Female; Membrane Transport Proteins/genetics/metabolism; Male; Age of Onset; Genetic Variation; NF-kappa B/metabolism; B-Lymphocytes/immunology/metabolism; Adolescent; THP-1 Cells; Interferon Type I/metabolism
Research Division(s): Inflammation
PubMed ID: 38831104
Publisher's Version: https://doi.org/10.1038/s41590-024-01846-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41590-024-01846-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-06-24 11:29:46

Last Modified: 2024-06-24 11:32:44