The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro
Authors' conclusion
Observations suggest that the private truncating TLR7 p.Glu834* variant associates with SLE-like clinical pictures through coupling with TLR8.
Study context
- Population
- Patients with juvenile-onset systemic lupus erythematosus (SLE) from the UK
- Participants
- 319 patients
Methodological detailstargeted new-generation sequencing, functional studies, molecular modelling
- Targeted new-generation sequencing
- Functional studies
- Molecular modelling
Main finding
As reported in the abstract
- Previously unreported private TLR7 coding variant p.Glu834* (heterozygous), introducing a stop codon, identified in a female patient with jSLE with multisystemic disease and a family history of lupus-like autoimmunity and premature deaths
- TLR7 p.Glu834* 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
- Elevated interferon (IFN) signature in peripheral blood cells from the patient, mirroring in vitro observations
- Molecular modelling: TLR8:TLR7 p.Glu834* heterodimer formation possible (shape complementarity), with more favourable interaction at the dimer interface than the endogenous TLR8:TLR8 dimer
- Patient born preterm, with neurodevelopmental delay and severe neuropsychiatric involvement
Original publication
The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro. Ann Rheum Dis. Published 22 August 2026. doi:10.
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