Abstract: FR-PO725

More Than C3 Deposition: The Unique Characteristics of One Family with C3 Glomerulopathy

Session Information

Category: Glomerular

  • 1004 Clinical/Diagnostic Renal Pathology and Lab Medicine

Authors

  • Leonhardt, Alexandria Isabeau clarissa, University of Iowa, Iowa City, Iowa, United States
  • Meyer, Nicole, University of Iowa, Iowa City, Iowa, United States
  • Borsa, Nicolò, The University of Iowa, Iowa City, Iowa, United States
  • Zhang, Yuzhou, University of Iowa, Iowa City, Iowa, United States
  • Smith, Richard J., University of Iowa, Iowa City, Iowa, United States
  • Nester, Carla M., University of Iowa, Iowa City, Iowa, United States
Background

As a disease, C3 Glomerulopathy is currently defined by the single diagnostic criteria of a predominant immune fluorescent staining of C3 on renal biopsy. Additonal diagnositic requirements have not been defined. After cases are ascertained, infrequently, it may be discovered that those affected have a genetic abnormality in a complement gene – supporting the underlying complement abnormality as the disease causing agent. We present a familial case of C3G identified after a proband with predominant C3 staining was discovered to have a homozygous C3 gene mutation.

Methods

After obtaining informed consent, a medical record review was completed on all available family members. The disease phenotype was confirmed by renal biopsies in persons with >1gm/24hr of urine protein. Comprehensive genetic screening was completed on all complement genes using standard procedures. An extensive complement analysis was performed that included serum levels of complement proteins and their cleavage products, assays of complement function, and screens for autoantibodies.

Results

A pathogenic variant in C3 segregated with each patient with a renal phenotype: c.443G>A, p.R148Q. Both the matriarch and patriarch of the family were heterozygous for this variant, consistent with their relationship as first cousins. The spectrum of clinical renal disease ranged from asymptomatic hematuria (N=2) or proteinuria (N=1) to end stage renal disease (N=3). One family member had multiple cysts by ultrasound. Renal biopsies confirmed C3GN in 3 family members and FSGS in a fourth person. Serum C3 levels were normal in all asymptomatic individuals (both with and without the variant). C3 levels were low in individuals with symptomatic C3GN pathology. All persons carrying the p.R148Q mutation had elevated serum levels of C3c. Surface plasmon resonance assays, as well as an expanded functional and cofactor assessment of the mutation is ongoing.

Conclusion

We present a rare case of familial C3 Glomerulpathy. Unique to this case is an underlying gene abnormality that segregates not only with the diagnostic C3G requirement, but also with FSGS and cystic renal disease. This pedigree highlights not only the narrow nature of the C3G definition, but also calls into question whether the C3 protein may play a functional role in other renal abnormalities.

Funding

  • NIDDK Support