Kong Na, Xu Qian, Shen Xiaoyue, Zhu Xiangyu, Cao Guangyi
Center for Reproductive Medicine and Obstetrics and Gynecology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, China.
Front Genet. 2023 Oct 16;14:1256549. doi: 10.3389/fgene.2023.1256549. eCollection 2023.
Empty follicle syndrome (EFS) is a rare condition in female infertility. It is characterized by the inability to retrieve oocytes from visibly large, normally developing follicles in the ovaries, despite ovarian stimulation. The genetic factors contributing to this syndrome remain unclear. This study focused on patients who underwent three consecutive ovarian stimulation procedures for oocyte retrieval but experienced unsuccessful outcomes, despite the presence of observable large follicles. Ultrasound examinations were conducted to assess follicular development during each procedure. In order to investigate potential genetic causes, we performed whole exome sequencing on peripheral blood samples from the patient. Interestingly, we identified that this patient carries a homozygous mutation in the genes. Within the gene, we identified a homozygous variant [NM_001110354.2, c.176T>A (p.L59H)] specifically located in the zona pellucida (ZP) domain. Further analysis, including bioinformatics methods and protein structure modeling, was carried out to investigate the conservation of the ZP3 variant across different species. This homozygous variant exhibited a high degree of conservation across various species. Importantly, the homozygous ZP3 variant was associated with the occurrence of empty follicle syndrome in affected female patients. The homozygous ZP3 variant represents a newly discovered genetic locus implicated in the development of human empty follicle syndrome. Our findings contribute to a deeper understanding of the role of zona pellucida-related genes in infertility and provide valuable insights for the genetic diagnosis of female infertility.
空卵泡综合征（EFS）是女性不孕症中的一种罕见病症。其特征是尽管进行了卵巢刺激，但仍无法从卵巢中明显可见的、正常发育的大卵泡中获取卵母细胞。导致该综合征的遗传因素尚不清楚。本研究聚焦于那些连续接受三次卵巢刺激以获取卵母细胞但结果均未成功的患者，尽管存在可观察到的大卵泡。在每次操作过程中均进行超声检查以评估卵泡发育情况。为了探究潜在的遗传原因，我们对患者的外周血样本进行了全外显子组测序。有趣的是，我们发现该患者在这些基因中存在纯合突变。在该基因内，我们鉴定出一个纯合变异体[NM_001110354.2，c.176T>A（p.L59H）]，其特异性地位于透明带（ZP）结构域。我们进一步开展了包括生物信息学方法和蛋白质结构建模在内的分析，以研究ZP3变异体在不同物种间的保守性。这种纯合变异体在各种物种中均表现出高度保守性。重要的是，纯合的ZP3变异体与受影响女性患者空卵泡综合征的发生有关。该纯合的ZP3变异体代表了一个新发现的与人类空卵泡综合征发生相关的遗传位点。我们的研究结果有助于更深入地理解透明带相关基因在不孕症中的作用，并为女性不孕症的基因诊断提供有价值的见解。
