CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis
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 dri...
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2021.670727/full |
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| author | Rossella Piras Matteo Breno Elisabetta Valoti Marta Alberti Paraskevas Iatropoulos Caterina Mele Elena Bresin Roberta Donadelli Paola Cuccarolo Richard J. H. Smith Ariela Benigni Giuseppe Remuzzi Marina Noris |
| author_facet | Rossella Piras Matteo Breno Elisabetta Valoti Marta Alberti Paraskevas Iatropoulos Caterina Mele Elena Bresin Roberta Donadelli Paola Cuccarolo Richard J. H. Smith Ariela Benigni Giuseppe Remuzzi Marina Noris |
| author_sort | Rossella Piras |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T19:26:45Z |
| format | Article |
| id | doaj.art-bf5651269e7640a2b06033b39950716b |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-19T19:26:45Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-bf5651269e7640a2b06033b39950716b2022-12-21T20:08:45ZengFrontiers Media S.A.Frontiers in Genetics1664-80212021-06-011210.3389/fgene.2021.670727670727CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative GlomerulonephritisRossella Piras0Matteo Breno1Elisabetta Valoti2Marta Alberti3Paraskevas Iatropoulos4Caterina Mele5Elena Bresin6Roberta Donadelli7Paola Cuccarolo8Richard J. H. Smith9Ariela Benigni10Giuseppe Remuzzi11Marina Noris12Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyMolecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, United StatesIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyIstituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, ItalyC3 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.https://www.frontiersin.org/articles/10.3389/fgene.2021.670727/fullC3 glomerulopathy (C3G)immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN)factor H (FH)factor H-related proteins (FHRs)complementcopy number variations (CNVs) |
| spellingShingle | Rossella Piras Matteo Breno Elisabetta Valoti Marta Alberti Paraskevas Iatropoulos Caterina Mele Elena Bresin Roberta Donadelli Paola Cuccarolo Richard J. H. Smith Ariela Benigni Giuseppe Remuzzi Marina Noris CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis Frontiers in Genetics C3 glomerulopathy (C3G) immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) factor H (FH) factor H-related proteins (FHRs) complement copy number variations (CNVs) |
| title | CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis |
| title_full | CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis |
| title_fullStr | CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis |
| title_full_unstemmed | CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis |
| title_short | CFH and CFHR Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis |
| title_sort | cfh and cfhr copy number variations in c3 glomerulopathy and immune complex mediated membranoproliferative glomerulonephritis |
| topic | C3 glomerulopathy (C3G) immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) factor H (FH) factor H-related proteins (FHRs) complement copy number variations (CNVs) |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2021.670727/full |
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