Piras Rossella, Breno Matteo, Valoti Elisabetta, Alberti Marta, Iatropoulos Paraskevas, Mele Caterina, Bresin Elena, Donadelli Roberta, Cuccarolo Paola, Smith Richard J H, Benigni Ariela, Remuzzi Giuseppe, Noris Marina
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.
Front Genet. 2021 Jun 11;12:670727. doi: 10.3389/fgene.2021.670727. eCollection 2021.
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 () and Factor B (), or in complement Factor H () and Factor I (), two genes that encode complement regulators. Copy number variations (CNVs) involving the -related genes () 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 region and characterize CNVs in a large cohort of patients with C3G ( = 103) and IC-MPGN ( = 96) compared to healthy controls ( = 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 in one patient with IC-MPGN; 2) an increased number of copies in one IC-MPGN and three C3G patients; 3) a deletion from -intron 3 to ' ( Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a hybrid gene in a C3G patient. This work highlights the contribution of CNVs to the pathogenesis of both C3G and IC-MPGN.
C3肾小球病（C3G）和免疫复合物介导的膜增生性肾小球肾炎（IC-MPGN）是罕见疾病，其特征是补体替代途径（AP）失调导致C3在肾小球沉积。在大约20%的受影响患者中，失调是由AP C3转化酶的两个成分即补体C3（）和B因子（），或补体H因子（）和I因子（）中的致病变异驱动的，这两个基因编码补体调节因子。在少数C3G患者中也描述了涉及产生杂交FHR蛋白的相关基因（）的拷贝数变异（CNV），但在IC-MPGN患者中未发现。在本研究中，我们使用多重连接依赖探针扩增（MLPA）来研究区域的基因组结构，并在一大群C3G患者（=103）和IC-MPGN患者（=96）中与健康对照（=100）相比表征CNV。我们在5例C3G患者和2例IC-MPGN患者中鉴定出导致结构变异（SV）的新/罕见CNV。使用长读长单分子实时测序（SMRT），我们检测到三个SV的断点。鉴定出的SV包括：1）一名IC-MPGN患者中整个的缺失；2）一名IC-MPGN患者和三名C3G患者中的拷贝数增加；3）一名C3G患者中从-内含子3到'（Δ）的缺失，导致FHR3-FHR1杂交蛋白；4）一名C3G患者中的杂交基因。这项工作突出了CNV对C3G和IC-MPGN发病机制的贡献。
