Functional Characterization of a Novel Intronic Complement Factor I Variant in Factor I Deficiency and Atypical...

Area of Science:

• Genetics
• Complement System Biology

Background:

• Noncanonical intronic splice site variants are implicated in atypical hemolytic uremic syndrome (aHUS).
• A previously identified intronic variant (c.328+42G>A) in the complement factor I (CFI) gene was found in a patient with Factor I (FI) deficiency.

Purpose of the Study:

• Identify additional carriers of the c.328+42G>A CFI variant.
• Functionally characterize the variant's impact on FI expression and its role in aHUS.

Main Methods:

• Screened a genetic registry for potential FI-driven pathologies.
• Conducted complement profiling and genetic analysis on carriers and family members.
• Utilized monocyte-derived dendritic cells (mo-DCs) and real-time PCR to investigate mRNA isoforms and nonsense-mediated decay (NMD).

Main Results:

• Identified 3 additional carriers, showing enrichment in the aHUS cohort.
• All carriers displayed significantly reduced FI levels.
• The variant induced aberrant splicing, producing a truncated FI transcript targeted by NMD, leading to near-complete FI loss.

Conclusions:

• The CFI c.328+42G>A variant causes FI deficiency through aberrant splicing and NMD.
• This variant may predispose individuals to aHUS, particularly in heterozygotes.
• Intronic region analysis is crucial for diagnosing complement-mediated diseases with unknown genetic causes.