Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome - PubMed
4 hours ago
- #gain-of-function
- #inflammatory syndrome
- #TLR8
- A novel gain-of-function TLR8 variant (A518T) was identified in two male siblings with severe inflammatory syndrome.
- The TLR8 A518T variant enhances NF-κB activation and increases proinflammatory cytokine secretion compared to wild-type TLR8.
- Protein degradation assays showed reduced abundance of the mutant TLR8 due to faster turnover and increased proteasomal degradation.
- Computational modeling predicted structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by A518T.
- The study integrates genetic, structural, functional, and clinical data to establish the pathogenicity of the TLR8 variant.