The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro.

OBJECTIVES: The X chromosome-linked Toll-like receptor (TLR)7 gene contributes to type I interferon (IFN) expression in systemic lupus erythematosus (SLE). Recently, ultra-rare variants in TLR7 have been linked with Mendelian forms of SLE. METHODS: Targeted new-generation sequencing was used to identify TLR7 coding variants in 319 patients with juvenile-onset (j)SLE from the UK. Functional studies investigated molecular impacts associated with a previoulsy unreported gene variant in TLR7. RESULTS: The previously unreported private TLR7 coding variant p.Glu834* (heterozygous), introducing a stop codon, was identified in a female patient with jSLE with multisystemic disease and a family history of lupus-like autoimmunity and premature deaths. The patient was born preterm and exhibited neurodevelopmental delay and severe neuropsychiatric involvement. On the molecular level, TLR7 p.Glu834* is associated with sustained interaction with the UNC93B1 chaperone, allowing endolysosomal integration and noncanonical dimerisation with TLR8, resulting in enhanced proinflammatory cytokine expression following TLR7/8 engagement. In vitro observations were mirrored by an elevated IFN signature in peripheral blood cells from the patient. Molecular modelling indicated that formation of the TLR8:TLR7 p.Glu834* heterodimer is possible because of the shape complementarity of TLR7 and TLR8, and a more favourable interaction at the dimer interface for the TLR8:TLR7 p.Glu834* as compared with the endogenous TLR8:TLR8 dimer. CONCLUSIONS: Observations suggest that the private truncating TLR7 p.Glu834* variant associates with SLE-like clinical pictures through coupling with TLR8. Findings expand the list of SLE-associated disease mechanisms and support genetic risk stratification and consideration of TLR and/or IFN-targeted treatments.