PDF(Pubmed)
Abstract：
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.
摘要：
UNC93B1是介导内体Toll样受体（TLR）信号传导的跨膜结构域蛋白。我们报告了五个拥有罕见错义替换的家庭(I317M，G325C,L330R,R466S,和R525P）在UNC93B1中引起系统性红斑狼疮（SLE）或冻疮性狼疮（CBL）为常染色体显性或常染色体隐性特征。至于导致鼠狼疮的D34A突变，我们记录了TLR7的增加，在较小程度上，在SLE的背景下,I317M(体外)和G325C(体外和离体)变体的TLR8活性。相反，在三个分离CBL的家庭中，L330R,R466S,和R525P变体在体外TLR7活性方面是同构的，对于R525P，离体。相反，这些变体显示TLR8活性的增加。我们观察到G325C的相互作用增强，L330R,和具有TLR8但不具有R525P取代的R466S变体，表明不同的疾病机制。总的来说,这些观察结果表明,由于TLR7和TLR8信号传导的差异增强,UNC93B1突变导致单基因SLE或CBL.
