Genetic and Acquired Abnormalities in C3 Glomerulopathy and Primary Immune Complex-Mediated MPGN

Piras, Rossella Alberta (2018). Genetic and Acquired Abnormalities in C3 Glomerulopathy and Primary Immune Complex-Mediated MPGN. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000da2c

Abstract

Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of glomerular injury that mainly occurs in children and young adults.

MPGN is currently classified in immune complex-mediated MPGN (IC-MPGN), characterized by activation of the complement classic pathway, and C3 Glomerulopathy (C3G), with predominant complement alternative pathway (AP) activation. C3G is further classified in Dense Deposit Disease (DDD) and C3 glomerulonephritis (C3GN).

The first part of the thesis describes a large cohort of patients with IC-MPGN (n=96), DDD (n=26) and C3GN (n=77). Data obtained from genetic and biochemical analysis were correlated with histological and clinical parameters. We found that the majority of patients across the three histology groups (from 70 to 85 %) showed low C3 and normal C4. About 18% of patients carried likely pathogenic variants (LPVs) in complement genes, mainly in CFH regulatory gene and in C3 and CFB, encoding the two convertase components. Interestingly, two LPVs in THBD gene, were identified in two patients with C3G. C3NeF, an autoantibody stabilizing AP convertase, resulted abundant in DDD patients (79%) but was also present in patients with IC-MPGN (40%) or C3GN (39%).

To classify IC-MPGN and C3G patients based on the underlying pathogenesis, a three-step algorithm based on histological, genetic and biochemical data was used to classify patients in 4 clusters identifying 4 different pathogenetic patterns.

In the second part of the thesis, copy number variation (CNV) studies, disclosed abnormal CNVs both in IC-MPGN and C3G. Interestingly, we describe, for the first time, genomic rearrangements involving the CFHR4 gene. Finally, Western Blot studies in DDD patients showed the presence of abnormal FHR molecular pattern in patients with normal CNVs and without CFHR LPVs.

In conclusion, the present study increased our understanding in IC-MPGN and C3G and provided new insights in the pathogenetic mechanisms underlying these complex glomerular diseases.