Abstract Background/Aims The Toll-like receptor (TLR)7 gene on the X chromosome-linked centrally contributes to type I interferon (IFN) expression. Recently, rare and common variants in TLR7 have been linked with the molecular pathophysiology of systemic lupus erythematosus (SLE). Methods This study investigated genetic variability of TLR7 in 319 juvenile-onset (j)SLE patients (51 boys, 268 girls) enrolled in the UK JSLE Cohort Study. Two ultra-rare variants (with minor allele frequencies 0.01) were identified and functionally investigated to test their impact on gene function and inflammatory cytokine expression. Results Previously unreported TLR7 coding variants p.Ser391* and p.Glu834* that introduce stop codons were identified in two jSLE patients from both sexes. The TLR7 p.Ser391* variant, deficient for the trans-membrane domain, failed to interact with the UNC93B1 chaperone protein (proximity ligation assays/PLA) resulting in reduced UNC93B1-mediated subcellular trafficking to the endo-lysosome (immunohistochemistry/IHC), accumulation in the endoplasmic reticulum (ER; IHC), ER stress with increased PERK phosphorylation (Western blotting) and type 1 interferon (IFN) expression (qRT-PCR). The TLR7 p.Glu834* variant allowed associations with UNC93B1 (PLA), mediating endo-lysosomal integration (IHC), dimerization with TLR8 (PLA), and IFN and NFkB dependent pro-inflammatory cytokine expression (qRT-PCR). Molecular modeling indicated that the formation of the TLR8/TLR7 p.Glu834* hetero-dimer was facilitated by shape complementarity, more favorable binding energetics, and increased structural similarity relative to wild-type TLR7. Conclusion This study suggests that (ultra-)rare TLR7 ‘loss-of-function’ variants associate with jSLE through alternative coupling with TLR8 (TLR7 p.Glu834*) and/or the induction of ER stress responses (TLR7 p.Ser391*). Observations expand the list of SLE-associated disease mechanisms and argue for genetic risk stratification and future consideration of TLR7, TLR8 and/or IFN-targeted treatments. Disclosure Y. Renaudineau: None. J. Hawkes: None. K. Mizgalska: None. V. Natoli: None. J. Roachdown: None. L. Cusin: None. F. Sposito: None. E. Sen: None. A. Kinder: None. M. Fusaro: None. W.H. Brooks: None. W. Guida: None. A. Karolak: None. A. Charras: None. M. Beresford: None. C.M. Hedrich: Grants/research support; Merck MISP to study lupus nephritis.
Renaudineau et al. (Wed,) studied this question.