Interface Gain-of-Function Mutations in TLR7 Cause Systemic and Neuro-inflammatory Disease

Area of Science:

• Immunology
• Genetics
• Autoimmune Diseases

Background:

• Toll-like receptor 7 (TLR7) recognizes single-stranded RNA (ssRNA), crucial for innate immunity against viruses.
• Gain-of-function mutations in TLR7 are linked to systemic lupus erythematosus (SLE) and neuromyelitis optica.
• TLR7's role in recognizing self-derived ssRNA contributes to autoimmune conditions.

Purpose of the Study:

• To identify and characterize novel mutations in the TLR7 gene.
• To investigate the impact of these mutations on TLR7 function and immune homeostasis.
• To explore the phenotypic spectrum associated with TLR7 gain-of-function mutations.

Main Methods:

• Identification of two novel TLR7 mutations: F507S and L528I.
• Analysis of mutation inheritance patterns within families, including X-linked inheritance.
• Prediction of altered TLR7 homo-dimerization and enhanced signaling based on mutation sites.

Main Results:

• The L528I mutation occurred de novo, while F507S was identified in a family with affected males, expanding known inheritance patterns.
• Mutations at residues 507 and 528 highlight the significance of the TLR7 dimerization interface.
• Altered homo-dimerization is predicted to enhance TLR7 signaling.

Conclusions:

• Novel TLR7 mutations F507S and L528I contribute to autoimmune diseases.
• These findings underscore the importance of the TLR7 dimerization interface in immune regulation.
• TLR7 gain-of-function mutations present a broader spectrum of disease, including significant neurological involvement, beyond SLE-like symptoms.