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

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. ### Competing Interest Statement S.L.M. is a scientific advisor for Odyssey therapeutics and NRG therapeutics. ### Funding Statement This study is supported by The National Natural Science Foundation of China (Grant number 32250410295, 82125015, 92042303), Guangzhou Women and Childrens Medical Center Fund. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Written informed consent has been obtained from the authorized individual for all participated patients. The Guangzhou Women and Childrens Medical Centre Medical Ethics Committee approved the study procedures ([2021]073B00) and ([2021]240A01) in consistence with Helsinki Declaration about ethics in using human samples. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes RNAseq datasets are submitted and the identifier will be included in the manuscript when published. All other data is available in the main text or the supplementary materials.