PATL 2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

Abstract

The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA‐binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects, respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA regulators) suggest an original role for Patl2 in mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2 −/− animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

ZNF354C is a transcriptional repressor that inhibits endothelial angiogenic sprouting

“…The RNA-seq analysis not only confirmed ZNF354C as a transcriptional repressor, it further led to the identification of target genes of ZNF354C. PATL2 is important for mammalian oocyte maturation whose removal causes oocyte meiotic deficiency in humans 21 . HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) is an E3 ubiquitin ligase which is upregulated by inflammatory cytokines in endothelial cells 22 .…”

Development of WEE2 kinase inhibitors as novel non-hormonal female contraceptives that target meiosis†

“…In addition to the studies from China that identified WEE2 mutations as a genetic basis for infertility, TFF has also been associated with mutations in PATL2 [ 48 ]. PALT2 functions as an oocyte specific RNA-binding protein [ 49–51 ]. Mutations in TUBB8, an oocyte-specific tubulin required to form the meiotic spindle, have also been identified in a cohort of Chinese patients with oocyte maturation defects [ 50 ].…”

Diversity of RNA-Binding Proteins Modulating Post-Transcriptional Regulation of Protein Expression in the Maturing Mammalian Oocyte

“…In order to explore the role of mammalian PATL2, our laboratory has recently studied the effects of Patl2 invalidation in mice. We showed that Patl2 invalidation leads to subfertility in females with oocytes showing dysregulation of a number of key transcripts expressed at various stages of oocyte maturation [40]. Fewer oocytes from Patl2 KO females mature to the MII stage and the rate of progression through the early embryo stages is significantly impacted.…”

“…A rarer type of human infertility is Oocyte Maturation Deficiency (OMD), a type of primary infertility characterised by the repetitive production of immature oocytes that do not mature in vitro. Invalidation of PATL2 has recently been associated with OMD in cases across several continents [40][41][42][43][44], with biallelic mutations associated with a GV-arrest phenotype and compound heterozygous mutations to a range of phenotypes from GV to early embryo arrest.…”