Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe...

Area of Science:

• Immunology
• Genetics
• Structural Biology

Background:

• Rare genetic variants in inborn errors of immunity (IEI) often lack clear clinical relevance.
• Multidisciplinary approaches integrating genetic, structural, functional, and clinical data are crucial for pathogenicity assessment.

Purpose of the Study:

• To investigate the pathogenicity of a novel TLR8 missense variant (A518T) found in two male siblings with recurrent infections and systemic inflammation.
• To characterize the functional and structural consequences of the TLR8 A518T variant.

Main Methods:

• Genetic sequencing to identify the variant.
• Functional assays measuring NF-κB activation and cytokine secretion.
• Protein degradation and turnover assays.
• Computational modeling of TLR8 structure.

Main Results:

• The TLR8 A518T variant demonstrated a gain-of-function effect, enhancing NF-κB activation and proinflammatory cytokine secretion.
• The mutant TLR8 protein exhibited reduced abundance due to increased proteasomal degradation and faster turnover.
• Computational modeling predicted enhanced structural stabilization of the TLR8 homodimer interface.

Conclusions:

• The study identifies a novel TLR8 ligand-specific gain-of-function mutation.
• This mutation contributes to complex immunopathology characterized by a proinflammatory immune signature and B cell dysregulation in affected siblings.