CFI – Complement Factor I and Atypical Hemolytic-Uremic Syndrome

Complement factor I (CFI) is a plasma serine protease that downregulates the alternative complement pathway by cleaving C3b and C4b. Heterozygous CFI mutations have been reported in patients with atypical hemolytic-uremic syndrome (aHUS), a thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The overall clinical validity of the CFI–aHUS association is classified as Strong based on identification of 23 unrelated probands harboring pathogenic CFI variants, recurrent post-transplant disease, and consistent functional impairment ([PMID:20016463]).

Genetic evidence supports an autosomal dominant inheritance with incomplete penetrance. In a cohort of 202 aHUS patients, 23 carried exonic CFI mutations including nonsense, frameshift, and missense variants leading to loss of function (LoF) or reduced protein levels ([PMID:20016463]). Segregation analysis in family studies demonstrated co-segregation of compound heterozygous CFI variants with disease in two affected relatives ([PMID:29940891]). Case series describe a total of 23 probands with heterozygous missense mutations, including one recurrent variant c.1106A>C (p.Tyr369Ser) identified in a renal transplant recipient with early aHUS recurrence ([PMID:18805611]).

Variant spectrum encompasses 24 missense and multiple LoF alleles across the serine protease domain and regulatory LDLRA domains. Reported variant classes include frameshift (e.g., c.188dup (p.Pro64fs)), splice site (c.1429+1G>C), nonsense (c.76G>T (p.Glu26Ter)), and hypomorphic missense changes. The selected representative variant is c.1106A>C (p.Tyr369Ser), a heterozygous missense change detected verbatim in a living related renal transplant recipient ([PMID:18805611]).

Functional studies demonstrate that many aHUS-associated CFI missense mutations impair FI secretion and cofactor activity. In vitro assays of eight secreted mutants showed marked reduction in C3b and C4b cleavage in the presence of factor H and MCP, consistent with haploinsufficiency ([PMID:19877009]). Cellular expression studies revealed that non-secreted mutants are retained in the endoplasmic reticulum, leading to quantitative FI deficiency. No animal models have been reported.

Conflicting evidence exists for the G261D (p.Gly261Asp) variant, which displayed normal FI plasma levels and unaltered C3b/C4b degradation in patient serum and recombinant assays, suggesting possible benign status ([PMID:17084897]).

In summary, heterozygous CFI mutations confer a strongly supported risk for aHUS via haploinsufficiency of FI and dysregulated complement activation. While most variants induce quantitative or functional deficiency, rare exceptions warrant careful evaluation. Incorporating CFI genetic screening into aHUS diagnostic workflows informs risk stratification and guides transplant and complement inhibitor therapy decisions.

Key Take-Home: CFI mutations should be screened in aHUS patients to identify those at high risk of recurrence and guide early anti-complement intervention.

References

• Journal of the American Society of Nephrology • 2010 • Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. PMID:20016463
• Molecular Immunology • 2008 • Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I. PMID:19877009
• American Journal of Kidney Diseases • 2009 • Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient. PMID:18805611
• Molecular Immunology • 2007 • A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. PMID:17084897

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