Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai, 200011, China.
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai, 200011, China; Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200439, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
Eur J Med Genet. 2022 Oct;65(10):104597. doi: 10.1016/j.ejmg.2022.104597. Epub 2022 Aug 25.
Premature ovarian insufficiency (POI) is a major cause of female subfertility. Although POI affects approximately 1-2% women worldwide, the etiology of a large number of POI patients remains unknown partially due to the genetic heterogeneity of POI. EIF4ENIF1 is one of the known POI-causative genes, and it plays an essential role in inhibiting mRNA translation and regulating mRNA destabilization in ovarian cells. In our study, two EIF4ENIF1 variants, c.9_11delGAG (p.R4del) (rs3834682) and c.2861G > C (p.G954A) (rs766008983) were identified in two sporadic Han Chinese POI patients through whole-exome sequencing. Both variants are rare in the human population. The two patients' mothers don't carry the rare variants and they have regular menstruation. The missense variant c.2861G > C was predicted to be deleterious by multiple bioinformatic tools. Western blot analysis further demonstrated that both of the two variants exhibited reduced mRNA and protein expression levels compared with the wild-type in vitro. Taken together, our findings reported two rare POI-associated EIF4ENIF1 variants, providing insights into genetic counseling and suggesting the contribution of EIF4ENIF1 variants in female infertility.
卵巢早衰（POI）是女性不孕的主要原因之一。尽管 POI 影响了全球约 1-2%的女性，但由于 POI 的遗传异质性，大量 POI 患者的病因仍不清楚。EIF4ENIF1 是已知的 POI 致病基因之一，它在抑制卵巢细胞中的 mRNA 翻译和调节 mRNA 不稳定性方面发挥着重要作用。在我们的研究中，通过全外显子测序在两名散发性汉族 POI 患者中鉴定出两个 EIF4ENIF1 变体，c.9_11delGAG (p.R4del) (rs3834682) 和 c.2861G > C (p.G954A) (rs766008983)。这两种变体在人群中均罕见。两名患者的母亲未携带这些罕见变体，且月经规律。错义变体 c.2861G > C 被多种生物信息学工具预测为有害。Western blot 分析进一步表明，与野生型相比，这两种变体在体外均表现出 mRNA 和蛋白表达水平降低。综上所述，我们的研究结果报道了两种罕见的与 POI 相关的 EIF4ENIF1 变体，为遗传咨询提供了新的见解，并提示 EIF4ENIF1 变体可能与女性不孕有关。
