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

Frontiers in Genetics

Roberta Donadelli¹  Marta Alberti¹  Ariela Benigni¹  Paraskevas Iatropoulos¹  Rossella Piras¹  Paola Cuccarolo¹  Giuseppe Remuzzi¹  Marina Noris¹  Matteo Breno¹  Caterina Mele¹  Elisabetta Valoti¹  Elena Bresin¹  Richard J. H. Smith² 

[1] Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy;Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, United States;

关键词: C3 glomerulopathy (C3G);    immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN);    factor H (FH);    factor H-related proteins (FHRs);    complement;    copy number variations (CNVs);   

DOI  :  10.3389/fgene.2021.670727

来源: DOAJ

【 摘 要 】

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 (CFHR34–6Δ) 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.

【 授权许可】

Unknown