Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases
Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases
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DOI：
10.1681/asn.2015050580
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发表时间：
2016-05-01
影响因子：
13.6
通讯作者：
Rodriguez de Cordoba, Santiago
中科院分区：
文献类型：
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作者：
Recalde, Sergio;Tortajada, Agustin;Rodriguez de Cordoba, Santiago
补体因子H （FH）突变R1210C与非典型溶血性尿毒症综合征（aHUS）相关，也会导致年龄相关性黄斑变性（AMD）的高风险，并与C3肾小球病变（C3G）相关。为了揭示这些关联的分子基础，并深入了解是什么决定了FH-R1210C携带者的疾病表型，我们在aHUS、C3G和AMD队列中鉴定了FH-R1210C携带者。在患者和亲属中确定的疾病状态显示，在aHUS队列中没有AMD表型，反之亦然，在AMD队列中缺乏肾脏疾病。这些发现与发生一种病理或另一种病理的突变携带者之间的r1210c独立的aHUS和AMD总体风险的差异是一致的。R1210C是一种不寻常的突变，在FH和HSA之间产生共价复合物。通过纯化的FH蛋白和表面等离子体共振分析，我们证明了这些FH- hsa复合物的形成损害了FH所有功能域的可及性。这些数据表明，R1210C是一种独特的c端FH突变，表现为部分FH缺陷，使个体易患具有不同潜在致病机制的多种病理；最终的疾病结局由不依赖r1210c的遗传风险因素决定。
The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of age related macular degeneration (AMD) and associates with C3 glomerulopathy (C3G). To reveal the molecular basis of these associations and to provide insight into what determines the disease phenotype in FH-R1210C carriers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts. Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort. These findings were consistent with differences in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pathology or the other. R1210C is an unusual mutation that generates covalent complexes between FH and HSA. Using purified FH proteins and surface plasmon resonance analyses, we demonstrated that formation of these FH-HSA complexes impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors.