UNC93B1 encodes an endoplasmic reticulum (ER) transmembrane protein involved in Toll-like receptor (TLR) trafficking from the ER to the endosomes. UNC93B1 recruits Syntenin-1 to its C-terminal end, where Syntenin-1 functions to inhibit TLR signaling. Variants in UNC93B1 were first reported in relation to SLE in 2024 (PMIDs: 38207055, 38780621, 38831104, 38869500).
Genetic evidence includes five missense variants and one in-frame insertion variant reported in six probands in four publications (PMIDs: 38207055, 38207015, 38780621, 38869500). Two and four of the variants were identified in a homozygous and heterozygous state, respectively, in the affected individuals. A case-control study using single-variant analysis for UNC93B1 reported an odds ratio of 17.9 for developing SLE (PMID: 38831104).
Experimental data includes evidence that UNC93B1 variants reported in patients increase TLR7 signaling. Direct protein-protein interactions of UNC93B1 with TLR7 and Syntenin-1 were confirmed (PMIDs: 19451267, 31546246). Mouse models introducing UNC93B1 variants known to cause upregulated TLR7 signaling resulted in multi-organ inflammation, glomerular disease, and positive autoantibodies (PMIDs: 38780621, 31546246, 38831104).
In summary, there is moderate evidence supporting the relationship between variants of UNC93B1 and a semidominant phenotype of Systemic Lupus Erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date April 9, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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