PDF(Pubmed)
Abstract：
Women undergoing controlled ovarian hyperstimulation prior to in vitro fertilization (IVF) are treated using various protocols to induce multiple follicular growths. Complete failure of all oocytes to mature during IVF cycles is rare; however, it is a known cause of primary female infertility. Recently, pathogenic variations in a few genes have been identified in women with oocyte maturation defects; however, the underlying genetic causes remain largely unknown.This study included a Turkish family comprising three sisters with recurring oocyte maturation arrest at the germinal vesicle stage after multiple ovarian stimulations. Exome sequencing revealed a homozygous missense variant (c.1037C>T, p.Ala346Val) in the EPAB gene (also known as PABPC1L) in all three affected sisters, which was either absent or heterozygous in the unaffected family members. Functional experiments confirming the pathogenicity of the variant were performed by transfecting HEK293T cells and demonstrated the instability and increased rate of proteolysis of the mutated PABPC1L/EPAB protein. The identified variant, located in the well-conserved fourth RNA recognition motif (RRM4), in silico 3D modelling suggested changes in the physical properties of the pathogenic variant of PABPC1L/EPAB. Our findings validate PABPC1L/EPAB as an essential genetic contributor to the oocyte maturation process in humans and have direct implications for the genetic counselling of patients and their family members.
摘要：
在体外受精（IVF）之前接受控制性卵巢过度刺激的妇女使用各种方案进行治疗，以诱导多个卵泡生长。在IVF周期中，所有卵母细胞完全不能成熟是罕见的;然而，它是原发性女性不孕的已知原因。最近,在有卵母细胞成熟缺陷的女性中已经发现了一些基因的致病变异;然而,潜在的遗传原因在很大程度上仍然未知。这项研究包括一个土耳其家庭，包括三个姐妹，在多次卵巢刺激后，在生发囊泡阶段反复出现卵母细胞成熟停滞。外显子组测序显示纯合错义变体（c.1037C>T，p.Ala346Val）在所有三个受影响的姐妹中的EPAB基因（也称为PABPC1L）中，在未受影响的家庭成员中不存在或杂合子。通过转染HEK293T细胞进行证实变体的致病性的功能实验,并证明突变的PABPC1L/EPAB蛋白的蛋白水解的不稳定性和增加的速率。确定的变体，位于保守的第四个RNA识别基序（RRM4）中，计算机3D建模表明PABPC1L/EPAB致病变体的物理性质发生了变化。我们的发现证实了PABPC1L/EPAB是人类卵母细胞成熟过程的重要遗传因素，并对患者及其家庭成员的遗传咨询具有直接意义。
