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

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.

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

“…Female mice with Pabpc1l knockout have been demonstrated to be infertile with complete arrest in MI and could not generate mature oocytes for fertilization 33,34 . However, recently, Wang et al reported that bi‐allelic pathogenic variants in PABPC1L caused human female infertility characterized by various phenotypes including oocyte maturation arrested at the GV or MI stage, fertilization failure, and early embryonic development arrest 36 . Wang et al also generated knock in (KI) mice model corresponding to the variants in their patients, and interestingly, the female KI mice ovulated mature MII oocytes after superovulation and the infertility was attributed to early embryonic arrest after IVF.…”

“…Female mice with global deletion of Pabpc1l were infertile and generated no mature oocytes or embryos in vivo or in vitro due to impaired translational activation, chromatin configuration, and transcriptional silencing 33–35 . However, to date, only one study has reported that variants in PABPC1L caused human female infertility 36 . More PABPC1L mutations need to be uncovered to confirm the relationship between PABPC1L and human fertility.…”

Female infertility from oocyte maturation arrest: assembling the genetic puzzle

“…The latter is particularly important for potential infertility alleles impacting gamete development or function because it is not yet feasible to accurately recapitulate gametogenesis in vitro . In this issue of EMBO Molecular Medicine , Wang et al ( 2023 ) present a comprehensive pipeline to identify and interpret pathogenic variants from infertility patients, using a degree of rigor that is exceptional for the reproductive genetics field.…”

“…In their study, Wang et al ( 2023 ) aimed to identify the genetic causes of OMA, a disease that results in female infertility and is a major contributor to in vitro fertilization failure. OMA can manifest at different stages of meiosis, and a few genes functioning in diverse processes such as recombination, spindle assembly, zona pellucida formation, and translational repression have been linked to OMA in women (Huang et al , 2014 ; Chen et al , 2017 ; Liu et al , 2017 ; Maddirevula et al , 2017 ; Dai et al , 2019 ; Zhang et al , 2020 ).…”

“…Wang et al ( 2023 ) conducted a thorough evaluation of potential OAM variants in PABPC1L . The study followed a four‐step approach (Fig 1 ).…”