Bi‐allelic pathogenic variants in PABPC1L cause oocyte maturation arrest and female infertility

Weijie Wang; Jing Guo; Juanzi Shi; Qun Li; Biaobang Chen; Zhiqi Pan; Ronggui Qu; Jing Fu; Rong Shi; Xia Xue; Jian Mu; Zhihua Zhang; Tianyu Wu; Wenjing Wang; Lin Zhao; Qiaoli Li; Lin He; Xiaoxi Sun; Qing Sang; Ge Lin; Lei Wang

doi:10.15252/emmm.202217177

EMBO Molecular Medicine (Apr 2023)

Bi‐allelic pathogenic variants in PABPC1L cause oocyte maturation arrest and female infertility

Weijie Wang,
Jing Guo,
Juanzi Shi,
Qun Li,
Biaobang Chen,
Zhiqi Pan,
Ronggui Qu,
Jing Fu,
Rong Shi,
Xia Xue,
Jian Mu,
Zhihua Zhang,
Tianyu Wu,
Wenjing Wang,
Lin Zhao,
Qiaoli Li,
Lin He,
Xiaoxi Sun,
Qing Sang,
Ge Lin,
Lei Wang

Affiliations

Weijie Wang: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Jing Guo: Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC‐Xiangya
Juanzi Shi: Reproductive Medicine Center, Shaanxi Maternal and Child Care Service Center
Qun Li: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Biaobang Chen: NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University
Zhiqi Pan: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Ronggui Qu: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Jing Fu: Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University
Rong Shi: Reproductive Medicine Center, Shaanxi Maternal and Child Care Service Center
Xia Xue: Reproductive Medicine Center, Shaanxi Maternal and Child Care Service Center
Jian Mu: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Zhihua Zhang: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Tianyu Wu: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Wenjing Wang: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Lin Zhao: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Qiaoli Li: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Lin He: Bio‐X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University
Xiaoxi Sun: Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University
Qing Sang: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University
Ge Lin: Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC‐Xiangya
Lei Wang: Institute of Pediatrics, Children’s Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University

DOI: https://doi.org/10.15252/emmm.202217177
Journal volume & issue: Vol. 15, no. 6
pp. 1 – 16

Abstract

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Abstract Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)‐binding protein in Xenopus, mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest in five individuals. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo, three strains of Pabpc1l knock‐in (KI) female mice were infertile. RNA‐sequencing analysis showed abnormal activation of the Mos‐MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility.

Published in EMBO Molecular Medicine

ISSN: 1757-4676 (Print); 1757-4684 (Online)
Publisher: Springer Nature
Country of publisher: United Kingdom
LCC subjects: Medicine: Medicine (General); Science: Biology (General): Genetics
Website: https://www.embopress.org/journal/17574684

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