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CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis.


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 (CFHR34 - 6 Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a CFHR31 - 5-CFHR410 hybrid gene in a C3G patient. This work highlights the contribution of CFH-CFHR CNVs to the pathogenesis of both C3G and IC-MPGN.

SUBMITTER: Piras R 

PROVIDER: S-EPMC8240960 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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<i>CFH</i> and <i>CFHR</i> Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis.

Piras Rossella R   Breno Matteo M   Valoti Elisabetta E   Alberti Marta M   Iatropoulos Paraskevas P   Mele Caterina C   Bresin Elena E   Donadelli Roberta R   Cuccarolo Paola P   Smith Richard J H RJH   Benigni Ariela A   Remuzzi Giuseppe G   Noris Marina M  

Frontiers in genetics 20210611


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 (<i>C3</i>) and Factor B (<i>CFB</i>), or in complement Factor H (<i>CFH</i>) and Factor I (<i>CFI</i>), two gen  ...[more]

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