The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro
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.
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BibTeX
@article{renaudineau2026private,
title = {{The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro}},
author = {Yves Renaudineau and Jenny Hawkes and Katarzyna Mizgalska and Valentina Natoli and Joni Roachdown and Lola Cusin and Francesca Sposito and Ethan Sen and Alison Kinder and Mathieu Fusaro and Wesley Brooks and Wayne Guida and Aleksandra Karolak and Amandine Charras and Michael Beresford and Christian Hedrich and Carla Roberts and Eslam Al-Abadi and Kate Armon and Kathryn Bailey and Coziana Ciurtin and Janet Gardner-Medwin and Kirsty Haslam and Daniel Hawley and Alice Leahy and Valentina Leone and Flora Mcerlane and Gita Modgil and Clarissa Pilkington and Athimalaipet Ramanan and Satyapal Rangaraj and Phil Riley},
journal = {Annals of the Rheumatic Diseases},
year = {2026},
month = sep,
doi = {10.1016/j.ard.2026.07.024},
url = {https://hal.science/hal-05757155v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - The private truncating Toll-like receptor 7 p.Glu834* variant associates with juvenile-onset systemic lupus erythematosus and pathological cytokine expression in vitro
AU - Yves Renaudineau
AU - Jenny Hawkes
AU - Katarzyna Mizgalska
AU - Valentina Natoli
AU - Joni Roachdown
AU - Lola Cusin
AU - Francesca Sposito
AU - Ethan Sen
AU - Alison Kinder
AU - Mathieu Fusaro
AU - Wesley Brooks
AU - Wayne Guida
AU - Aleksandra Karolak
AU - Amandine Charras
AU - Michael Beresford
AU - Christian Hedrich
AU - Carla Roberts
AU - Eslam Al-Abadi
AU - Kate Armon
AU - Kathryn Bailey
AU - Coziana Ciurtin
AU - Janet Gardner-Medwin
AU - Kirsty Haslam
AU - Daniel Hawley
AU - Alice Leahy
AU - Valentina Leone
AU - Flora Mcerlane
AU - Gita Modgil
AU - Clarissa Pilkington
AU - Athimalaipet Ramanan
AU - Satyapal Rangaraj
AU - Phil Riley
PY - 2026
DA - 2026/09/21
JO - Annals of the Rheumatic Diseases
DO - 10.1016/j.ard.2026.07.024
UR - https://hal.science/hal-05757155v1
AB - 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.
SN - 0003-4967
SN - 1468-2060
ER -