CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative
Rossella Piras1, Matteo Breno1, Elisabetta Valoti1
1Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
Insights
Copy number variations in the CFH-CFHR region contribute to rare kidney diseases C3 Glomerulopathy (C3G) and IC-MPGN. These genetic changes impact complement pathway regulation, leading to glomerular C3 deposition and disease development.
Area of Science:
- Nephrology
- Genetics
- Immunology
Background:
- C3 Glomerulopathy (C3G) and Immune Complex-Mediated Membranoproliferative glomerulonephritis (IC-MPGN) are rare kidney diseases driven by complement alternative pathway dysregulation.
- Pathogenic variants in complement genes (C3, CFB, CFH, CFI) and copy number variations (CNVs) in CFH-related genes (CFHRs) are implicated in C3G pathogenesis.
- The role of CFH-CFHR CNVs in IC-MPGN has been less understood.
Purpose of the Study:
- To investigate the genomic architecture of the CFH-CFHR region and characterize CNVs in a large cohort of C3G and IC-MPGN patients.
- To identify novel structural variants (SVs) and their contribution to the pathogenesis of C3G and IC-MPGN.
Main Methods:
- Multiplex Ligation-dependent Probe Amplification (MLPA) was used to analyze CNVs in the CFH-CFHR region.
- Long-read single molecule real-time sequencing (SMRT) was employed to detect breakpoints of identified SVs.
- A cohort of 103 C3G patients, 96 IC-MPGN patients, and 100 healthy controls were studied.
Main Results:
- New/rare CNVs leading to SVs were identified in 5 C3G and 2 IC-MPGN patients.
- Identified SVs included a complete CFH deletion in an IC-MPGN patient, increased CFHR4 copies in IC-MPGN and C3G patients, and CFHR3 deletions/hybrids in C3G patients.
- These CNVs result in altered complement regulatory proteins, including hybrid FHR proteins.
Conclusions:
- CFH-CFHR CNVs are significant contributors to the pathogenesis of both C3G and IC-MPGN.
- The study expands the understanding of genetic underpinnings of these rare complement-mediated kidney diseases.
- Structural variants in the CFH-CFHR locus represent a crucial mechanism in the development of C3G and IC-MPGN.
Abstract:
C3 Glomerulopathy (C3G) and Immune Complex-Mediated Membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases characterized by glomerular deposition of C3 caused by dysregulation of the alternative pathway (AP) of complement. In approximately 20% of affected patients, dysregulation is driven by pathogenic variants in the two components of the AP C3 convertase, complement C3 (C3) and Factor B (CFB), or in complement Factor H (CFH) and Factor I (CFI), two genes that encode complement regulators. Copy number variations (CNVs) involving the CFH-related genes (CFHRs) that give rise to hybrid FHR proteins also have been described in a few C3G patients but not in IC-MPGN patients. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to study the genomic architecture of the CFH-CFHR region and characterize CNVs in a large cohort of patients with C3G (n = 103) and IC-MPGN (n = 96) compared to healthy controls (n = 100). We identified new/rare CNVs resulting in structural variants (SVs) in 5 C3G and 2 IC-MPGN patients. Using long-read single molecule real-time sequencing (SMRT), we detected the breakpoints of three SVs. The identified SVs included: 1) a deletion of the entire CFH in one patient with IC-MPGN; 2) an increased number of CFHR4 copies in one IC-MPGN and three C3G patients; 3) a deletion from CFHR3-intron 3 to CFHR3-3'UTR (CFHR3 Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a CFHR3 hybrid gene in a C3G patient. This work highlights the contribution of CFH-CFHR CNVs to the pathogenesis of both C3G and IC-MPGN.
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