Complement Factor I Variants in Complement-Mediated Renal Diseases.

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are rare kidney diseases driven by complement alternative pathway dysregulation.
• Complement Factor I (FI) is crucial for downregulating complement activity, and its dysfunction is linked to C3G and aHUS pathogenesis.

Purpose of the Study:

• To investigate the functional activity of select CFI missense variants in patients with C3G and aHUS.
• To correlate CFI variants with disease phenotype and identify contributing genetic factors.

Main Methods:

• Identified patients with rare CFI variants (MAF < 0.1%) from C3G and aHUS cohorts.
• Performed comprehensive complement analyses, including biomarker profiling and pathway activity assays.
• Developed and utilized a novel FI functional assay for 40 patients.

Main Results:

• Seventy-eight percent of rare CFI variants were associated with reduced FI protein levels (31/40), with 22 cases below the normal range.
• Two variants with normal FI levels demonstrated reduced FI activity (type 2 variants).
• No patients had known autoantibodies; disease phenotype varied significantly based on co-inherited genetic variants in other complement genes (e.g., CD46, C3, CFH).

Conclusions:

• Rare CFI variants predispose to C3G and aHUS, but the clinical phenotype is strongly influenced by the genetic background.
• Isolated rare CFI variants typically lead to aHUS, while co-inheritance with CD46 loss-of-function variants results in earlier onset aHUS.
• Co-inheritance with C3 gain-of-function variants shifts the phenotype to C3G, highlighting the multifactorial nature of these diseases.