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Pathogenic missense variation in PABPC1L/EPAB causes female infertility due to oocyte maturation arrest at the germinal vesicle stage

  • Genetics
  • Published:
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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.

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Data availability

Data generated in this study are included in the following article and corresponding supplementary data. The raw sequencing data generated in the course of this study are not publicly available due to research protocol restrictions with patient informed consent not covering this data distribution. The identified variant has been submitted to ClinVar (VCV001172840.1) (https://www.ncbi.nlm.nih.gov/clinvar).

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Acknowledgements

We would like also to thank Dr. Robert Drillien for his critical reading of this manuscript.

Funding

The study was funded by Fondation Maladie Rares (High Throughput Sequencing and Rare Diseases–2018, “GenOmics of rare diseases”).

Author information

Authors and Affiliations

  1. Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (H.U.B), Hôpital Erasme, Service de Gynécologie-Obstetrique, Clinique de Fertilité, Route de Lennik, 808, 1070, Brussels, Belgium

    O. Okutman

  2. Novafertil IVF Center, Konya, Turkey

    A. S. Gürbüz

  3. Department of Molecular Biology and Genetics, Institute of Graduate Studies in Sciences, Istanbul University, Istanbul, Turkey

    U. Büyük

  4. Laboratoire de Génétique Médicale LGM, Institut de Génétique Médicale d’Alsace IGMA, INSERM UMR 1112, Université de Strasbourg, Strasbourg, France

    E. Real, R. Leconte, J. Muller, N. Le May & S. Viville

  5. Complex Systems and Translational Bioinformatics, ICube UMR 7357, Université de Strasbourg, 67000, Strasbourg, France

    K. Chennen & C. Mayer

  6. UFR Sciences de La Vie, Université Paris Cité, 75013, Paris, France

    C. Mayer

  7. Unité Fonctionnelle de Bioinformatique Médicale Appliquée Au Diagnostic (UF7363), Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    J. Muller

  8. Laboratoire de Diagnostic Génétique, Unité de Génétique de L’infertilité (UF3472), Hôpitaux Universitaires de Strasbourg, 67091, Strasbourg, France

    S. Viville

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  1. O. Okutman
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  10. S. Viville
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Contributions

OO data analysis, variation confirmation; ASG recruitment of patients, collection of clinical data and samples; UB DNA extraction, quality and quantity control; JM supervised the bioinformatics analysis; ER performed the assays using humanized yeast cells and analyzed the data; NLM and RL performed the HEK293T cell assays, ER performed the yeast experiments, and KC performed the sequence alignments and analysis; CM performed the 3D modeling and analysis; SV supervised all the study. OO and SV designed and wrote the first draft of the manuscript. All authors contributed to the revision process and agreed to the last version of the manuscript.

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Correspondence to S. Viville.

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Okutman, O., Gürbüz, A.S., Büyük, U. et al. Pathogenic missense variation in PABPC1L/EPAB causes female infertility due to oocyte maturation arrest at the germinal vesicle stage. J Assist Reprod Genet 41, 311–322 (2024). https://doi.org/10.1007/s10815-023-03009-1

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