Exome sequencing identifies a novel gene, WNK1, for susceptibility to pelvic organ prolapse (POP).
Exome sequencing identifies a novel gene, WNK1, for susceptibility to pelvic organ prolapse (POP).
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DOI：
10.1371/journal.pone.0119482
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Rao S;Lang J;Zhu L;Chen J
盆腔器官脱垂（POP）是一种常见的妇科疾病；然而，遗传成分在很大程度上仍未确定。外显子组测序因其高染色体覆盖率和准确性而被广泛用于识别多种疾病的致病基因突变。在这项研究中，我们首次对来自代表性 POP 病例的 8 个外周血 DNA 样本进行了全外显子组测序 (WES)。过滤来自 dbSNP 数据库（版本 138）和千人基因组计划的测序数据后，通过 Sanger 测序鉴定并进一步验证了 WNK1 中的 2 个错义变异，即 c.2668G > A (p.G890R) 和 c.6761C> T (p.P2254L)。在验证阶段，在 161 名 POP 患者中的 11 名患者中检测到 c.2668G > A (p.G890R) 变体和 8 个其他变体。 231 名健康对照者中不存在所有这些变异。功能实验表明，与健康对照的成纤维细胞相比，带有 WNK1 突变的 POP 子宫骶韧带的成纤维细胞表现出松散且不规则的排列。综上所述，我们的研究发现了一个新的POP易感基因WNK1，扩大了POP的致病突变谱，为未来POP的基因诊断和医疗管理提供了依据。
Pelvic organ prolapse (POP) is a common gynecological disorder; however, the genetic components remain largely unidentified. Exome sequencing has been widely used to identify pathogenic gene mutations of several diseases because of its high chromosomal coverage and accuracy. In this study, we performed whole exome sequencing (WES), for the first time, on 8 peripheral blood DNA samples from representative POP cases. After filtering the sequencing data from the dbSNP database (build 138) and the 1000 Genomes Project, 2 missense variants in WNK1, c.2668G > A (p.G890R) and c.6761C> T (p.P2254L), were identified and further validated via Sanger sequencing. In validation stage, the c.2668G > A (p.G890R) variant and 8 additional variants were detected in 11 out of 161 POP patients. All these variants were absent in 231 healthy controls. Functional experiments showed that fibroblasts from the utero-sacral ligaments of POP with WNK1 mutations exhibited loose and irregular alignment compared with fibroblasts from healthy controls. In sum, our study identified a novel gene, WNK1, for POP susceptibility, expanded the causal mutation spectrums of POP, and provided evidence for the genetic diagnosis and medical management of POP in the future.
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