C3 – C3 Glomerulonephritis

C3 glomerulonephritis (C3GN) is a rare renal disorder defined by dominant C3 fragment deposition within glomerular capillary walls and mesangium, often with scant immunoglobulin staining on biopsy and electron-dense deposits in subendothelial, subepithelial, and mesangial locations. Patients typically present with microscopic hematuria, proteinuria, nephrotic syndrome, or acute kidney injury against a backdrop of hypocomplementemia, reflecting dysregulated activation of the alternative complement pathway ([PMID:29592796]). Chronic infection or inflammation may trigger complement overactivity in genetically predisposed individuals, as exemplified by a cystic fibrosis patient with persistent microscopic hematuria and proteinuria associated with profound terminal complex activation (sC5b-9 1588 ng/ml; normal < 400 ng/ml) ([PMID:29592796]).

Genetic analyses across unrelated cases have implicated heterozygous C3 missense variants in C3GN pathogenesis. Two probands harbored rare coding changes: c.304C>G (p.Arg102Gly) in a cystic fibrosis patient ([PMID:29592796]), and c.1774C>T (p.Arg592Trp) in a familial case presenting with nephrotic syndrome and acute kidney injury ([PMID:28614243]). A cohort study of 85 C3GN patients identified additional C3 allele variants/polymorphisms in a subset with concomitant autoimmune features, suggesting a potential trigger role for systemic immune activation ([PMID:26187133]). No loss-of-function or structural variants have been recurrently reported in C3GN to date.

Inheritance is consistent with autosomal dominant transmission exhibiting incomplete penetrance. Segregation analysis in the familial report showed the c.1774C>T (p.Arg592Trp) variant in one unaffected daughter, with no additional affected relatives identified despite testing nine family members ([PMID:28614243]). This limited co-segregation underscores variable expressivity and the necessity of integrating genetic findings with clinical and complement functional data.

Functional evidence supports a gain-of-function mechanism whereby C3 variants impair regulatory interactions—particularly with factor H—leading to enhanced alternative pathway amplification. Elevated systemic sC5b-9 levels and mesangial C3 deposition demonstrate concordance between human pathology and complement overactivation assays. Structural studies of analogous C3 mutations have shown conformational alterations in macroglobulin domains that disrupt factor H cofactor activity, bolstering the mechanistic link to glomerular injury.

No studies to date have refuted the association of C3 variants with C3GN or identified loss-of-function alleles causing disease. However, incomplete penetrance and variable presentation warrant careful interpretation of genetic results, and further segregation data are needed to clarify familial risk.

In summary, heterozygous missense variants in C3 contribute to C3 glomerulonephritis by dysregulating the alternative complement pathway, manifesting as proteinuria, nephrotic syndrome, and acute kidney injury in an autosomal dominant manner with incomplete penetrance. Genetic testing for C3 variants—coupled with complement functional assays—can guide diagnosis, inform prognosis, and identify candidates for complement-targeted therapies.

Key take-home: C3GN arises from gain-of-function C3 variants that enhance alternative pathway activation; integrating genetic and functional data is critical for accurate diagnosis and personalized management.

References

• BMC Nephrology • 2018 • C3 glomerulopathy in cystic fibrosis: a case report. PMID:29592796
• Medicine • 2017 • Different types of glomerulonephritis associated with the dysregulation of the complement alternative pathway in 2 brothers: A case report. PMID:28614243
• Journal of Nephrology • 2016 • C3 glomerulonephritis and autoimmune disease: more than a fortuitous association? PMID:26187133

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