Chauvet Sophie, Roumenina Lubka T, Bruneau Sarah, Marinozzi Maria Chiara, Rybkine Tania, Schramm Elizabeth C, Java Anuja, Atkinson John P, Aldigier Jean Claude, Bridoux Frank, Touchard Guy, Fremeaux-Bacchi Veronique
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France;
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1064, Institut de Transplantation Urologie-Nephrologie, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France;
J Am Soc Nephrol. 2016 Jun;27(6):1665-77. doi: 10.1681/ASN.2015040348. Epub 2015 Oct 15.
C3 glomerulopathy is a recently described form of CKD. C3GN is a subtype of C3 glomerulopathy characterized by predominant C3 deposits in the glomeruli and is commonly the result of acquired or genetic abnormalities in the alternative pathway (AP) of the complement system. We identified and characterized the first mutation of the C3 gene (p. I734T) in two related individuals diagnosed with C3GN. Immunofluorescence and electron microscopy studies showed C3 deposits in the subendothelial space, associated with unusual deposits located near the complement receptor 1 (CR1)-expressing podocytes. In vitro, this C3 mutation exhibited decreased binding to CR1, resulting in less CR1-dependent cleavage of C3b by factor 1. Both patients had normal plasma C3 levels, and the mutant C3 interacted with factor B comparably to wild-type (WT) C3 to form a C3 convertase. Binding of mutant C3 to factor H was normal, but mutant C3 was less efficiently cleaved by factor I in the presence of factor H, leading to enhanced C3 fragment deposition on glomerular cells. In conclusion, our results reveal that a CR1 functional deficiency is a mechanism of intraglomerular AP dysregulation and could influence the localization of the glomerular C3 deposits.
C3肾小球病是一种最近才被描述的慢性肾脏病形式。C3肾小球肾炎（C3GN）是C3肾小球病的一种亚型，其特征是肾小球中主要有C3沉积，通常是补体系统替代途径（AP）获得性或遗传性异常的结果。我们在两名被诊断为C3GN的相关个体中鉴定并表征了C3基因的首个突变（p.I734T）。免疫荧光和电子显微镜研究显示C3沉积于内皮下间隙，与表达补体受体1（CR1）的足细胞附近的异常沉积物相关。在体外，这种C3突变与CR1的结合减少，导致因子I对C3b的CR1依赖性裂解减少。两名患者的血浆C3水平均正常，突变型C3与因子B的相互作用与野生型（WT）C3相当，以形成C3转化酶。突变型C3与因子H的结合正常，但在因子H存在的情况下，突变型C3被因子I裂解的效率较低，导致C3片段在肾小球细胞上的沉积增加。总之，我们的结果表明，CR1功能缺陷是肾小球内AP失调的一种机制，可能影响肾小球C3沉积物的定位。
