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.

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