LHX8 杂合性功能丧失变异导致以卵母细胞成熟阻滞为特征的女性不孕。
Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest.
机构信息
Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China.
Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China; Human Phenome Institute, Fudan University, Shanghai, China.
出版信息
Genet Med. 2022 Nov;24(11):2274-2284. doi: 10.1016/j.gim.2022.07.027. Epub 2022 Aug 27.
PURPOSE
The genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test.
METHODS
Through comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes.
RESULTS
A total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg138∗], c.282C>A [p.Cys94∗]; c.257dup [p.Tyr86∗]; and c.180del, [p.Ser61Profs∗30]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.
CONCLUSION
By combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.
目的
卵母细胞成熟阻滞导致女性不孕的遗传原因在很大程度上尚不清楚，并且尚未在不孕患者队列中应用基于人群的遗传分析。我们旨在通过基于基因的负担测试来鉴定导致卵母细胞成熟阻滞的新的致病基因。
方法
通过比较 716 名具有卵母细胞成熟阻滞特征的不孕女性和 3539 名对照的外显子测序数据，我们进行了基于基因的负担测试，并鉴定出一个新的致病基因 LHX8。使用小基因测定评估剪接事件，在 HeLa 细胞中评估 LHX8 蛋白的表达，并在 HeLa 细胞和小鼠卵母细胞中确定核亚细胞定位。
结果
从 6 个独立的家系中总共鉴定出 5 个杂合性丧失功能的 LHX8 变体（c.389+1G>T、c.412C>T[p.Arg138∗]、c.282C>A[p.Cys94∗]；c.257dup[p.Tyr86∗]和 c.180del[p.Ser61Profs∗30]）。LHX8 中鉴定出的所有变体均产生截短的 LHX8 蛋白，并导致 LHX8 在 HeLa 细胞和小鼠卵母细胞中的核定位丢失。
结论
通过结合遗传证据和功能评估，我们鉴定出一个新的致病基因 LHX8，并建立了 LHX8 单倍不足与卵母细胞成熟阻滞导致的女性不孕之间的因果关系。
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