Xiao Xue, Ghossein Cybele, Tortajada Agustín, Zhang Yuzhou, Meyer Nicole, Jones Michael, Borsa Nicolo Ghiringhelli, Nester Carla M, Thomas Christie P, de Córdoba Santiago Rodríquez, Smith Richard J H
Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA; Interdepartmental PhD Program in Genetics, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
Department of Medicine, Division of Nephrology and Hypertension Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Mol Immunol. 2016 Sep;77:89-96. doi: 10.1016/j.molimm.2016.07.007. Epub 2016 Aug 1.
C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1-4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.
C3肾小球病（C3G）是一种极为罕见的补体介导的肾脏疾病，其组织学特征是肾小球内C3沉积占主导地位。C3G的家族性病例极为罕见，为深入了解补体失调的遗传驱动因素提供了独特视角。在本报告中，我们描述了一名患有C3G的患者。由于一名亲属也患有同样的疾病，我们试图寻找潜在的遗传共性来解释这种表型。作为全面基因筛查的一部分，我们完成了补体因子H相关区域的多重连接依赖性探针扩增，并鉴定出与基因组重排一致的扩增改变。通过比较基因组杂交，我们缩小并克隆了重排断点，从而确定了一个新的融合基因，该基因可翻译为一种血清蛋白，由因子H相关蛋白5（短共识重复序列1和2）和因子H相关蛋白2（短共识重复序列1 - 4）组成。这些数据突出了因子H相关蛋白在补体活性控制中的作用，并阐明了这种控制的扰动如何导致C3G。
