Annals of the rheumatic diseases · 2026
The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro.
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Renaudineau Yves, Hawkes Jenny, Mizgalska Katarzyna, Natoli Valentina, Roachdown Joni, Cusin Lola, Sposito Francesca, Sen Ethan, Kinder Alison, Fusaro Mathieu, Brooks Wesley H, Guida Wayne, Karolak Aleksandra, Charras Amandine, Beresford Michael W, Hedrich Christian M, UK JSLE Cohort Study
Аннотация
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.
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.