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

Okutman O., Gürbüz A., Büyük U., Real E., Leconte R., Chennen K., ...More

Journal of Assisted Reproduction and Genetics, vol.41, no.2, pp.311-322, 2024 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 41 Issue: 2
  • Publication Date: 2024
  • Doi Number: 10.1007/s10815-023-03009-1
  • Journal Name: Journal of Assisted Reproduction and Genetics
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, ATLA Religion Database, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.311-322
  • Keywords: EPAB, Female infertility, Genetics, GV, Immature oocyte, PABPC1L
  • Istanbul University Affiliated: Yes


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.