The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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.
Source: Annals of the Rheumatic Diseases
Authors: Yves Renaudineau, Jenny Hawkes, Katarzyna Mizgalska, Valentina Natoli, Joni Roachdown, Lola Cusin, Francesca Sposito, Ethan Sen, Alison Kinder, Mathieu Fusaro, Wesley H. Brooks, Wayne Guida, Aleksandra Karolak, Amandine Charras, Michael W. Beresford, Christian M Hedrich, Carla Roberts, Eslam Al-Abadi, Kate Armon, Kathryn Bailey, Coziana Ciurtin, Janet Gardner-Medwin, Kirsty Haslam, Daniel P. Hawley, Alice Leahy, Valentina Leone, Flora McErlane, Gita Modgil, Clarissa Pilkington, Athimalaipet V. Ramanan, Satyapal Rangaraj, Phil Riley
Institutions: Centre National de la Recherche Scientifique, Université Toulouse III - Paul Sabatier, Inserm, Centre Hospitalier Universitaire de Toulouse, Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, University of Liverpool, University of South Florida, Moffitt Cancer Center, Centre Hospitalier Universitaire Vaudois, University of Genoa, Royal Victoria Infirmary, Great North Children's Hospital, Newcastle University, Leicester Royal Infirmary, Alder Hey Children's NHS Foundation Trust, Birmingham Children's Hospital, Cambridge University Hospitals NHS Foundation Trust, National Health Service, University of Oxford, Oxford University Hospitals NHS Trust, University College London, University of Glasgow, Bradford Royal Infirmary, Sheffield Children's Hospital, Southampton General Hospital, Leeds Teaching Hospitals NHS Trust, Musgrove Park Hospital, Great Ormond Street Hospital, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Nottingham University Hospitals NHS Trust, Royal Manchester Children's Hospital
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,870
OpenAlex ID: W7203975646