Logo image
Back
Ultra-rare C3 mutation leading to a dominant familial C3 glomerulopathy phenotype
Abstract   Peer reviewed

Ultra-rare C3 mutation leading to a dominant familial C3 glomerulopathy phenotype

Alexandria Leonhardt, Jill Hauer, Nicolo Ghiringhelli, Yuzhou Zhang, Nicole Meyer, Renee X. Goodfellow, Bertha Martin, Carla Nester and Richard Smith
Molecular immunology, Vol.89, pp.175-176
09/2017
DOI: 10.1016/j.molimm.2017.06.158

View Online

Abstract

Background: Families segregating C3 glomerulopathy (C3G) are exceedingly rare. When identified, the identified pathogenic driver has most frequently been a genomic rearrangement of the complement factor H-related genes, which gives rise to novel fusion proteins. Mutations in the convertase genes C3 and CFB are uncommon. Herein, we present a family segregating a complex renal phenotype that included C3 glomerulonephritis (C3GN) and focal segmental glomerulosclerosis (FSGS). Materials and 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 >1 g/24 h of urine protein. Because multiple persons segregated renal disease, an underlying genetic commonality was suspected and comprehensive genetic screening was completed on all complement genes using standard procedures. In addition, 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 and conclusions: A pathogenic variant was identified in C3 that segregated with the 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. One family member with asymptomatic hematuria (unbiopsied) expired from meningococcal meningitis at the age of 15. The spectrum of renal disease ranged from asymptomatic hematuria (N = 2) or proteinuria (N = 1) to end stage renal disease (N = 3). Renal biopsies confirmed C3GN in 3 family members and FSGS in a fourth person. All persons carrying the p.R148Q mutation had elevated serum levels of C3c; in addition, serum levels of C3 were low in all persons with a more severe renal phenotype. The location of the mutation in MG2 domain of C3 suggests that the interaction of C3 with factor H is impaired. Surface plasmon resonance assays, as well as an expanded functional and cofactor assessment of the mutation, are ongoing.

Details

Metrics

11 Record Views
Logo image