Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest
Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest
复制标题
PATL2 的双等位基因突变导致女性不孕，其特征是卵母细胞成熟停滞
DOI：
10.1016/j.ajhg.2017.08.018
复制
发表时间：
2017-10-05
影响因子：
9.8
通讯作者：
Wang, Lei
中科院分区：
文献类型：
--
作者：
Chen, Biaobang;Zhang, Zhihua;Wang, Lei
卵母细胞成熟的停滞会导致女性不育症，但人类卵母细胞成熟停滞的遗传决定因素仍然在很大程度上未知。以前，我们确定了负责人卵母细胞成熟停滞的TUBB8突变，表明遗传因素在该疾病中的重要作用。但是，TUBB8突变仅占卵母细胞成熟滞留的人的30％。因此，该疾病可能涉及其他尚不清楚的遗传因素。在这里，我们最初确定了patl2（c.784c> t [p。Arg262*]）的纯合无义突变，该家族具有由人卵母细胞生发囊泡（GV）滞留为特征的表型。随后在179个个体中对PATL2进行的突变筛选确定了其他四个具有略有表型变异性的复合杂合PATL2突变的独立个体。遗传负担测试进一步证实了PATL2对人卵母细胞成熟停滞的遗传贡献。通过HeLa细胞中的蛋白质印迹，鉴定受影响个体的颗粒细胞中的剪接事件，以及受影响个体卵母细胞的免疫染色，我们提供了证据表明PATL2中的突变导致蛋白质量减少。这些发现表明，PATL2突变在卵母细胞成熟停滞中的重要作用，并扩展了我们对女性不育症遗传基础的理解。
Oocyte maturation arrest results in female infertility, but the genetic determinants of human oocyte maturation arrest remain largely unknown. Previously, we identified TUBB8 mutations responsible for human oocyte maturation arrest, indicating the important role of genetic factors in the disorder. However, TUBB8 mutations account for only around 30% of individuals with oocyte maturation arrest; thus, the disorder is likely to involve other genetic factors that are as yet unknown. Here, we initially identified a homozygous nonsense mutation of PATL2 (c.784C>T [p. Arg262*]) in a consanguineous family with a phenotype characterized by human oocyte germinal vesicle (GV) arrest. Subsequent mutation screening of PATL2 in a cohort of 179 individuals identified four additional independent individuals with compound-heterozygous PATL2 mutations with slight phenotypic variability. A genetic burden test further confirmed the genetic contribution of PATL2 to human oocyte maturation arrest. By western blot in HeLa cells, identification of splicing events in affected individuals' granulosa cells, and immunostaining in affected individuals' oocytes, we provide evidence that mutations in PATL2 lead to decreased amounts of protein. These findings suggest an important role for PATL2 mutations in oocyte maturation arrest and expand our understanding of the genetic basis of female infertility.