Gene SymbolCFI
Full NameComplement Factor I
Chromosomal Location4p25.3
Ensembl IDENSG00000167644
Associated DiseasesAge-Related Macular Degeneration, Complement Deficiency
The CFI gene encodes complement factor I, a serine protease that plays a critical role in regulating all three complement pathways. Factor I cleaves and inactivates C3b and C4b, requiring cofactors for its activity. The gene is located on chromosome 4p25.3 and encodes a protein of 406 amino acids [1].
Factor I is a member of the serine protease family and circulates in plasma at low concentrations (~35 μg/mL). It is synthesized primarily in the liver but is also expressed in various tissues including the brain. The protein consists of a heavy chain (containing the protease domain) and a light chain (containing the cofactor domains) held together by a disulfide bond [2].
Factor I is the only known protease that can cleave C3b and C4b, but requires cofactor proteins for its activity:
-
C3b Cleavage: Factor I cleaves C3b at specific sites, generating inactive C3b (iC3b)
- Requires cofactors: CFH, MCP (CD46), C4BP, CR1
- Cleavage sites: Arg1281, Arg1298, Arg1299
-
C4b Cleavage: Factor I inactivates C4b
- Requires cofactors: C4BP, CR1
- Generates C4c and C4d fragments
-
Limited C5 Cleavage: Factor I can also cleave C5 (limited activity)
- Does not generate functional C5a
- May regulate terminal pathway activation
- Controls amplification of all complement pathways
- Prevents immune complex deposition
- Protects host tissues from complement-mediated damage
- Essential for immune homeostasis
- CFI variants have been implicated in AD risk in genome-wide studies
- Altered CFI levels observed in AD cerebrospinal fluid
- CFI may interact with complement activation in AD neuroinflammation
- The role of CFI in amyloid clearance is under investigation [3]
- CFI variants are associated with AMD risk, particularly in European populations [4]
- Loss-of-function CFI variants increase AMD susceptibility
- CFI polymorphisms interact with CFH variants in AMD risk
- Therapeutic targeting of CFI is being explored for AMD treatment
- CFI deficiency is a rare autosomal recessive disorder
- Leads to recurrent bacterial infections
- Increased risk of autoimmune disease
- Presents with angioedema and lupus-like symptoms
- Glomerulonephritis: CFI mutations associated with renal disease
- Infection Susceptibility: Particularly with encapsulated bacteria
- Liver: Primary site of synthesis (hepatocytes)
- Brain: Low baseline expression in astrocytes and microglia
- Kidney: Expression in tubular epithelial cells
- Immune cells: Monocytes and macrophages
CFI expression is regulated by:
- Inflammatory cytokines (IL-6, IFN-γ) upregulate CFI
- Acute phase response increases CFI levels
- Glucocorticoids suppress CFI expression
- TGF-β can modulate CFI expression
- G119R: Common variant affecting enzyme activity
- A252G: Polymorphism in the signal peptide region
- R399Q: Variant associated with AMD risk
- CFI polymorphisms vary across populations
- Certain variants enriched in European populations
- Serum CFI levels can be measured
- Genetic testing available for CFI variants
- Functional assays for CFI activity
- Recombinant CFI replacement therapy (experimental)
- Small molecule inhibitors for complement diseases
- Gene therapy approaches under investigation
- NCBI Gene: CFI (3426)
- UniProt: Complement factor I (P05156)
- Zhou et al., Complement factor I in Alzheimer's disease (2018)
- Kavanagh et al., Complement factor I and AMD (2013)
- Rozemuller et al., Complement in neurodegeneration (2011)
- Skerka et al., Complement factor I mutations (2013)