COL4A3 mutations cause focal segmental glomerulosclerosis (vol 6, pg 498, 2014)
COL4A3 mutations cause focal segmental glomerulosclerosis (vol 6, pg 498, 2014)
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COL4A3 突变导致局灶节段性肾小球硬化（第 6 卷，第 498 页，2014 年）
DOI：
10.1093/jmcb/mjv023
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发表时间：
2015
影响因子：
5.5
通讯作者：
Chen Nan
中科院分区：
文献类型：
--
作者：
Xie Jingyuan;Wu Xiaoxi;Ren Hong;Wang Weiming;Wang Zhaohui;Pan Xiaoxia;Hao Xu;Tong Jun;Ma Jun;Ye Zhibin;Meng Guoyu;Zhu Yufei;Kiryluk Krzysztof;Kong Xiangyin;Hu L;ian;Chen Nan
局灶节段性肾小球硬化症（FSGS）是一种组织学上可识别的肾小球损伤，常导致蛋白尿和肾功能衰竭。为了确定其致病基因，对一个大型中国队列进行了全外显子组测序和桑格测序，该队列包括40个FSGS家族，50名散发性FSGS患者，9名独立的常染色体隐性Alport综合征（ARAS）患者和190名种族匹配的健康对照。排除了有肾外表现的患者，这些表现表明有系统性疾病或其他已知的遗传性肾脏疾病。在5个（12.5%）FSGS家系和1个（2%）散发性FSGS患者中发现了COL4A3的异质性突变。所有发现的突变都破坏了高度保守的蛋白质序列，并且在公共数据库或190名健康对照中都没有发现。在COL4A3异质性突变的FSGS患者中，仅在有电子显微镜检查结果的患者中检测到肾小球基底膜（GBM）节段性变薄。5例ARAS患者（55.6%）在COL4A3或COL4A4中存在纯合子或复合杂合子突变。在ARAS患者中，分别有100%、80%和40%的患者出现GBM、听力损失和眼部异常的严重变化。总的来说，一个新的FSGS患者亚组是由异质性COL4A3突变引起的，这种突变在被诊断为遗传性FSGS的家族中相对频繁。因此，我们建议在家族性FSGS患者中筛查COL4A3突变。
Focal segmental glomerulosclerosis (FSGS) is a histologically identifiable glomerular injury often leading to proteinuria and renal failure. To identify its causal genes, whole-exome sequencing and Sanger sequencing were performed on a large Chinese cohort that comprised 40 FSGS families, 50 sporadic FSGS patients, 9 independent autosomal recessive Alport's syndrome (ARAS) patients, and 190 ethnically matched healthy controls. Patients with extrarenal manifestations, indicating systemic diseases or other known hereditary renal diseases, were excluded. HeterozygousCOL4A3mutations were identified in five (12.5%) FSGS families and one (2%) sporadic FSGS patient. All identified mutations disrupted highly conserved protein sequences and none of them was found in either public databases or the 190 healthy controls. Of the FSGS patients with heterozygousCOL4A3mutations, segmental thinning of the glomerular base membrane (GBM) was only detected in the patient with electronic microscopy examination results available. Five ARAS patients (55.6%) had homozygous or compound-heterozygous mutations inCOL4A3orCOL4A4. Serious changes in the GBM, hearing loss, and ocular abnormalities were found in 100%, 80%, and 40% of the ARAS patients, respectively. Overall, a new subgroup of FSGS patients resulting from heterozygousCOL4A3mutations was identified.The mutations are relatively frequent in families diagnosed with inherited forms of FSGS. Thus, we suggest screening forCOL4A3mutations in familial FSGS patients.