Identification of nonfunctional PABPC1L causing oocyte maturation abnormalities and early embryonic arrest in female primary infertility,Clinical Genetics

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Identification of nonfunctional PABPC1L causing oocyte maturation abnormalities and early embryonic arrest in female primary infertility
Clinical Genetics ( IF 2.9 ) Pub Date : 2023-09-18 , DOI: 10.1111/cge.14425
Xiang Wang ₁ , Ruixi Zhou ₂ , Xiaowei Lu ₃ , Siyu Dai ₁ , Mohan Liu ₁ , Chuan Jiang ₁ , Yanting Yang ₄ , Ying Shen _{1,

5} , Yan Wang ₆ , Hanmin Liu _{5,

7}

Affiliation

Oocyte maturation arrest, fertilization failure, and early embryonic arrest are important causes of female infertility, whereas the genetic events that contribute to these processes are largely unknown. Loss-of-function of PABPC1L in mice has been suggested to cause female infertility involved in the absence of mature oocytes or embryos in vivo or in vitro. However, the role of PABPC1L in human female reproduction remains largely elusive. In this study, we identified a homozygous missense mutation (c.536G>A, p.R179Q) and a compound heterozygous mutation (c.793C>T, p.R265W; c.1201C>T, p.Q401*) in PABPC1L in two unrelated infertile females characterized by recurrent oocyte maturation abnormalities and early embryonic arrest. These variants resulted in nonfunctional PABPC1L protein and were associated with impaired chromatin configuration and transcriptional silencing in GV oocytes. Moreover, the binding capacity of mutant PABPC1L to mRNAs related to oocyte maturation and early embryonic development was decreased significantly. Our findings revealed novel PABPC1L mutations causing oocyte maturation abnormalities and early embryonic arrest, confirming the essential role of PABPC1L in human female fertility.

中文翻译：

鉴定导致女性原发性不孕症卵母细胞成熟异常和早期胚胎停滞的无功能 PABPC1L

卵母细胞成熟停滞、受精失败和早期胚胎停滞是女性不孕的重要原因，而导致这些过程的遗传事件在很大程度上是未知的。小鼠体内 PABPC1L 功能丧失被认为会导致女性不孕，这与体内或体外成熟卵母细胞或胚胎的缺乏有关。然而，PABPC1L 在人类女性生殖中的作用仍然很大程度上难以捉摸。在本研究中，我们在PABPC1L中鉴定出纯合错义突变 (c.536G>A，p.R179Q) 和复合杂合突变 (c.793C>T，p.R265W；c.1201C>T，p.Q401*)两名不相关的不育女性的特征是反复出现卵母细胞成熟异常和早期胚胎停滞。这些变异导致 PABPC1L 蛋白无功能，并与 GV 卵母细胞染色质构型受损和转录沉默相关。此外，突变型PABPC1L与卵母细胞成熟和早期胚胎发育相关mRNA的结合能力显着降低。我们的研究结果揭示了新的PABPC1L突变导致卵母细胞成熟异常和早期胚胎停滞，证实了PABPC1L在人类女性生育力中的重要作用。

更新日期：2023-09-18

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