Journal article
CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis
Frontiers in genetics, Vol.12, pp.670727-670727
06/11/2021
DOI: 10.3389/fgene.2021.670727
PMCID: PMC8240960
PMID: 34211499
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
4
–
6
Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a
CFHR3
1
–
5
-CFHR4
10
hybrid gene in a C3G patient. This work highlights the contribution of
CFH-CFHR
CNVs to the pathogenesis of both C3G and IC-MPGN.
Details
- Title: Subtitle
- CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis
- Creators
- Rossella Piras - Mario Negri Institute for Pharmacological ResearchMatteo Breno - Mario Negri Institute for Pharmacological ResearchElisabetta Valoti - Mario Negri Institute for Pharmacological ResearchMarta Alberti - Mario Negri Institute for Pharmacological ResearchParaskevas Iatropoulos - Mario Negri Institute for Pharmacological ResearchCaterina Mele - Mario Negri Institute for Pharmacological ResearchElena Bresin - Mario Negri Institute for Pharmacological ResearchRoberta Donadelli - Mario Negri Institute for Pharmacological ResearchPaola Cuccarolo - Mario Negri Institute for Pharmacological ResearchRichard J. H Smith - Roy J. and Lucille A. Carver College of MedicineAriela Benigni - Mario Negri Institute for Pharmacological ResearchGiuseppe Remuzzi - Mario Negri Institute for Pharmacological ResearchMarina Noris - Mario Negri Institute for Pharmacological Research
- Resource Type
- Journal article
- Publication Details
- Frontiers in genetics, Vol.12, pp.670727-670727
- DOI
- 10.3389/fgene.2021.670727
- PMID
- 34211499
- PMCID
- PMC8240960
- NLM abbreviation
- Front Genet
- ISSN
- 1664-8021
- eISSN
- 1664-8021
- Publisher
- Frontiers Media S.A
- Language
- English
- Date published
- 06/11/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256928902771
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