Marinozzi Maria Chiara, Vergoz Laura, Rybkine Tania, Ngo Stephanie, Bettoni Serena, Pashov Anastas, Cayla Mathieu, Tabarin Fanny, Jablonski Mathieu, Hue Christophe, Smith Richard J, Noris Marina, Halbwachs-Mecarelli Lise, Donadelli Roberta, Fremeaux-Bacchi Veronique, Roumenina Lubka T
Institut National de la Santé et de la Recherche Médicale UMRS 1138, Cordeliers Research Center, Complement and Diseases Team, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France;
Institut National de la Santé et de la Recherche Médicale UMRS 1138, Cordeliers Research Center, Complement and Diseases Team, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (Paris-6), Paris, France;
J Am Soc Nephrol. 2014 Sep;25(9):2053-65. doi: 10.1681/ASN.2013070796. Epub 2014 Mar 20.
Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association.
非典型溶血性尿毒症综合征（aHUS）是一种与补体替代途径过度激活相关的遗传性超罕见肾脏疾病。在因子B（FB）配体结合位点已鉴定出四个功能获得性突变，这些突变形成了高活性或失调的C3转化酶。在此，我们研究了最近从不同aHUS队列中鉴定出的10个FB基因变化的功能后果。通过对替代C3和C5转化酶形成及调节的多项检测，我们鉴定出两个功能获得性且可能与疾病相关的突变，它们分别形成了一种高活性转化酶（M433I）或一种对FH介导的衰变具有抗性的转化酶（K298Q）。一个突变（R178Q）产生了一种部分裂解的蛋白，该蛋白无配体结合或功能活性。与第7位最常见的多态性R7相比，七个基因变化导致配体结合和功能活性接近正常或仅略有降低。值得注意的是，用于预测FB突变与疾病相关性的算法均未完全与实验数据一致，这表明应谨慎采用计算机模拟方法。这些数据与先前发表的结果相结合，表明在aHUS患者中鉴定出的15个FB基因变化中有9个与疾病发病机制无关。这项研究强调，对FB中已鉴定的核苷酸变化进行功能评估对于确认疾病关联至关重要。
