CFHR5 – C3 Glomerulonephritis

CFHR5 variants have been reported in two unrelated individuals presenting with C3 glomerulonephritis characterized by nephrotic syndrome and persistent hypocomplementemia. Both cases involved heterozygous missense changes (c.805T>C (p.Cys269Arg) and c.508G>A (p.Val170Met)) without family segregation studies (PMID:24536001, PMID:34238373). Given fewer than three families and absence of segregation, the overall CFHR5–C3 glomerulonephritis association is classified as Limited.

Autosomal dominant inheritance is suggested by heterozygous variants with no additional affected relatives reported. The variant spectrum includes two missense changes in CFHR5 (c.805T>C (p.Cys269Arg); c.508G>A (p.Val170Met)). Clinical features comprise periorbital edema and nephrotic syndrome (HP:0100539; HP:0000100). No recurrent or founder alleles have been documented in C3GN cohorts.

Functional studies demonstrate that CFHR5 normally binds properdin and regulates complement activation on renal surfaces. Disease-associated CFHR5 hybrid proteins (CFHR2–CFHR5Hyb and CFHR5Dup) form large oligomers with enhanced properdin recruitment and increased local C3b and C5b-9 deposition in vitro and in patient kidney tissue, consistent with a gain-of-function mechanism (PMID:26432903). Structural analysis of a duplication mutant (c.59-1806_430+3225dup) reveals a compact dimer accommodating extra C3b binding sites, rationalizing dysregulated complement activation in CFHR5 nephropathy (PMID:32928961).

No conflicting reports specifically refute the role of CFHR5 variants in C3 glomerulonephritis. While CFHR5 alterations are also observed in atypical hemolytic uremic syndrome and IgA nephropathy, these do not negate its pathogenic contribution to C3GN.

Overall, CFHR5–C3 glomerulonephritis meets Limited clinical validity based on two probands and lacking segregation data, supported by moderate functional evidence of gain-of-function complement dysregulation. Further family studies and additional cohorts are needed to strengthen this association.

Key Take-home: Heterozygous CFHR5 missense variants likely contribute to C3 glomerulonephritis via a gain-of-function mechanism that enhances complement activation, supporting inclusion of CFHR5 in diagnostic genetic panels and guiding complement-targeted therapies.

References

• Journal of nephrology • 2014 • A novel CFHR5 mutation associated with C3 glomerulonephritis in a Turkish girl. PMID:24536001
• European journal of medical research • 2021 • Co-existence of Alport syndrome and C3 glomerulonephritis in a proband with family history. PMID:34238373
• Journal of the American Society of Nephrology • 2016 • Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces. PMID:26432903
• The Journal of biological chemistry • 2020 • The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy. PMID:32928961

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