Identification of a novel TLR7 gain-of-function variant that underlies systemic lupus erythematosus

Gain-of-function (GOF) variants in human TLR7 have recently been reported in 11 cases, six of which were diagnosed with systemic lupus erythematosus (SLE). We have identified the X-linked L840R TLR7 variant in hemizygosity in a male patient with SLE and in heterozygosity in his clinically asymptomatic mother. The leucine 840 is located at the first amino acid of TLR7 transmembrane domain and is conserved across various species. The L840R substitution is predicted to be deleterious by various scoring algorithms and may therefore affect TLR7 function. Molecular dynamics simulations of TLR7–UNC93B1 interactions revealed that R840 alters nearby amino acids interactions, resulting in increased hydrogen bond between E834 of TLR7 with R157 of UNC93B1. Finally, the L840R TLR7 variant has increased activity compared with WT, as measured with a nuclear factor κB (NF-κB)–specific luciferase reporter upon stimulation with TLR7 agonist R848. Hence, hemizygosity for L840R confers GOF for NF-κB activation and underlies SLE by potentially increasing TLR7 binding to UNC93B1.