BACKGROUND This study wants to know the genetic cause of preeclampsia (PE) which is a leading cause of maternal and perinatal death, but the underlying molecular mechanisms that cause PE remain poorly understood. Many single nucleotide polymorphisms have been identified by genome-wide association studies and were found to be associated with PE; however, few studies have used whole-exome sequencing (WES) to identify PE variants. METHODS Five patients with severe early-onset preeclampsia (EOPE) were recruited, and WES was performed on each patient. Sanger sequencing was used to confirm the potential causative genetic variant. RESULTS After a stringent bioinformatics analysis, a rare variant in the GOT1 gene, c.44C > G:p.P15R, was found in one patient. Bioinformatics analysis showed that the variant site is highly conserved across several species and was predicted to be a pathogenic variant according to several online mutational function prediction software packages. Further structural biology homology modeling suggested that P15R would change the electric environment of enzymatic center, and might affect the binding affinity of substrate or product. CONCLUSION We demonstrated for the first time that the variant in GOT1 may be associated with EOPE, the results of this study provide researchers and clinicians with a better understanding of the molecular mechanisms that underlie maternal severe EOPE.

中文翻译：

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通过全外显子组测序确定的与早期发作的严重先兆子痫相关的母体GOT1新型变异体。

背景技术这项研究想知道先兆子痫（PE）的遗传原因，它是孕产妇和围产期死亡的主要原因，但是引起PE的潜在分子机制仍然知之甚少。通过全基因组关联研究已鉴定出许多单核苷酸多态性，并发现它们与PE相关。但是，很少有研究使用全外显子组测序（WES）来鉴定PE变异体。方法招募5例重度早发先兆子痫（EOPE）患者，并对每位患者进行WES。Sanger测序被用于确认潜在的致病基因变异。结果经过严格的生物信息学分析，在一名患者中发现了GOT1基因的罕见变异，即c.44C> G：p.P15R。生物信息学分析表明，该变异位点在多个物种中高度保守，并且根据一些在线突变功能预测软件包预测为致病变异。进一步的结构生物学同源性建模表明，P15R会改变酶中心的电环境，并可能影响底物或产物的结合亲和力。结论我们首次证明了GOT1的变异可能与EOPE有关，这项研究的结果使研究人员和临床医生对孕产妇严重EOPE的分子机制有了更好的了解。进一步的结构生物学同源性建模表明，P15R会改变酶中心的电环境，并可能影响底物或产物的结合亲和力。结论我们首次证明了GOT1的变异可能与EOPE有关，这项研究的结果使研究人员和临床医生对孕产妇严重EOPE的分子机制有了更好的了解。进一步的结构生物学同源性建模表明，P15R会改变酶中心的电环境，并可能影响底物或产物的结合亲和力。结论我们首次证明了GOT1的变异可能与EOPE有关，这项研究的结果使研究人员和临床医生对孕产妇严重EOPE的分子机制有了更好的了解。