Genetic, molecular and functional analyses of complement factor I deficiency.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Factor I (FI) deficiency leads to uncontrolled alternative complement pathway activation, increasing infection susceptibility.
• Genetic analysis identified mutations in patients with near-complete or undetectable serum FI.
• Understanding these mutations is crucial for diagnosing and managing complement deficiencies.

Observation:

• Mutations were introduced into recombinant FI for functional and expression studies.
• Specific mutations (G170V, Q232K, C237Y, S250L, I339M, H400L) affected protein expression, secretion, or degradation of complement components C4b and C3b.
• A truncated mutant (Q336x) was non-functional due to the absence of the serine protease domain.

Findings:

• The G170V mutation prevented protein expression.
• Mutations Q232K, C237Y, S250L, I339M, and H400L impaired recombinant Factor I secretion.
• Mutants C237Y and S250L showed reduced degradation of C4b and C3b, while Q336x was expressed but non-functional.

Implications:

• This research provides the first functional characterization of molecular defects in complete Factor I deficiency.
• Findings clarify the pathogenic mechanisms of FI mutations, aiding in diagnosis and potential therapeutic strategies.
• Understanding genotype-phenotype correlations in FI deficiency is essential for patient management.