David Clémence, Arango-Franco Carlos A, Badonyi Mihaly, Fouchet Julien, Rice Gillian I, Didry-Barca Blaise, Maisonneuve Lucie, Seabra Luis, Kechiche Robin, Masson Cécile, Cobat Aurélie, Abel Laurent, Talouarn Estelle, Béziat Vivien, Deswarte Caroline, Livingstone Katie, Paul Carle, Malik Gulshan, Ross Alison, Adam Jane, Walsh Jo, Kumar Sathish, Bonnet Damien, Bodemer Christine, Bader-Meunier Brigitte, Marsh Joseph A, Casanova Jean-Laurent, Crow Yanick J, Manoury Bénédicte, Frémond Marie-Louise, Bohlen Jonathan, Lepelley Alice
Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, INSERM UMR1163, Paris, France.
Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France.
J Exp Med. 2024 Aug 5;221(8). doi: 10.1084/jem.20232066. Epub 2024 Jun 13.
UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in UNC93B1 causing systemic lupus erythematosus (SLE) or chilblain lupus (CBL) as either autosomal dominant or autosomal recessive traits. As for a D34A mutation causing murine lupus, we recorded a gain of TLR7 and, to a lesser extent, TLR8 activity with the I317M (in vitro) and G325C (in vitro and ex vivo) variants in the context of SLE. Contrastingly, in three families segregating CBL, the L330R, R466S, and R525P variants were isomorphic with respect to TLR7 activity in vitro and, for R525P, ex vivo. Rather, these variants demonstrated a gain of TLR8 activity. We observed enhanced interaction of the G325C, L330R, and R466S variants with TLR8, but not the R525P substitution, indicating different disease mechanisms. Overall, these observations suggest that UNC93B1 mutations cause monogenic SLE or CBL due to differentially enhanced TLR7 and TLR8 signaling.
UNC93B1是一种跨膜结构域蛋白，介导内体Toll样受体（TLR）的信号传导。我们报告了五个家族，其UNC93B1中存在罕见的错义替代（I317M、G325C、L330R、R466S和R525P），导致系统性红斑狼疮（SLE）或冻疮样狼疮（CBL），呈现常染色体显性或常染色体隐性遗传特征。至于导致小鼠狼疮的D34A突变，在SLE背景下，我们记录到I317M（体外）和G325C（体外和体内）变体使TLR7活性增强，TLR8活性也有一定程度增强。相反，在三个分离出CBL的家族中，L330R、R466S和R525P变体在体外对TLR7活性是同构的，对于R525P变体在体内也是如此。相反，这些变体表现出TLR8活性增强。我们观察到G325C、L330R和R466S变体与TLR8的相互作用增强，但R525P替代没有，这表明存在不同的疾病机制。总体而言，这些观察结果表明，UNC93B1突变由于TLR7和TLR8信号传导的差异增强而导致单基因SLE或CBL。
