A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H-Related 3 Gene in Atypical Hemolytic Uremic Syndrome
A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H-Related 3 Gene in Atypical Hemolytic Uremic Syndrome
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DOI：
10.1681/asn.2015010100
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发表时间：
2016-06-01
影响因子：
13.6
通讯作者：
Kavanagh, David
中科院分区：
文献类型：
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作者：
Challis, Rachel C.;Araujo, Geisilaine S. R.;Kavanagh, David
位于染色体 1q32 的补体激活调控簇包含补体因子 H (CFH) 和 5 个补体因子 H 相关 (CFHR) 基因。基因组的这个区域源自几个大的基因组重复，这些低拷贝重复可能导致该区域的基因组不稳定。影响这些基因的基因组疾病已在非典型溶血性尿毒症综合征中得到描述，通常由非等位基因同源重组引起。我们描述了一种新的 CFH/CFHR3 杂合基因，其继发于 6.3-kb 从头缺失，该缺失是通过微同源介导的末端连接而不是非等位基因同源重组产生的。我们确认了该杂合基因的转录本，并显示出一种分泌蛋白产物，该产物缺乏 H 因子的识别域，并且表现出细胞表面补体调节受损。该杂合基因的形成作为从头事件出现的事实表明，该簇是基因组的动态区域，其中可能出现其他基因组疾病。
The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.