Journal Article

PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

Martinez, Guillaume, Arnoult, Christophe, Le Blévec, Emilie, Kherraf, Zine‐Eddine, Makni, Mounir, Zouari, Raoudha, Amiri‐Yekta, Amir, Boguenet, Magalie, Cedrin Durnerin, Isabelle, Conne, Béatrice, Coutton, Charles, Nef, Serge, Fourati Ben Mustapha, Selima, Latrous, Habib, Assou, Said, Christou‐Kent, Marie, Issartel, Jean Paul, Guttin, Audrey, Bottari, Serge P, Thierry‐Mieg, Nicolas, Ray, Pierre F, Kharouf, Mahmoud, Halouani, Lazhar, Lambert, Emeline, Marrakchi, Ouafi, Escoffier, Jessica, Karaouzène, Thomas

2018

Overview

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. Synopsis A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation. In a cohort of 23 infertile women from North Africa with oocyte meiotic deficiency (OMD), a truncating mutation in the gene PATL2 , encoding an RNA‐binding protein, was identified in 26% of patients. Patl2 knockout female mice presented severe subfertility, confirming the human diagnostic. Patl2 knockout mouse oocytes could progress to the MII stage, however with numerous morphological defects hampering normal fertilisation and development. Patl2 is not detectable in primordial follicle oocytes, but is strongly expressed during oocyte growth and remains detectable at least until the MII stage. Patl2 has a unique expression pattern from primordial follicle‐stage to MII‐stage oocytes and did not colocalise with Cpeb1, Msy2 or Ddx6 known to stabilise mRNA during oocyte growth. Patl2 deficiency leads to a down or up‐regulation of a subset of mRNAs encoding proteins which are crucial for oocyte meiotic progression and early embryonic development, with no effect on the GV‐MII transition. Graphical Abstract A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation.

• Publisher: Nature Publishing Group UK,Wiley Open Access,John Wiley and Sons Inc,Springer Nature
• Subject: Adult / Animals / Biochemistry, Molecular Biology / Codon, Nonsense / Cohort Studies / Development Biology / EMBO16 / EMBO45 / Exome Sequencing - methods / Female / female sterility / Gametogenesis / Gene Expression Profiling - methods / Genomics / Humans / Infertility - genetics / Life Sciences / Meiosis - genetics / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Nuclear Proteins - genetics / Nuclear Proteins - physiology / oocyte developmental competence / oocyte maturation arrest / oocyte maturation failure / Oocytes - cytology / Oocytes - metabolism / Patl2 / Research Article / RNA-Binding Proteins - genetics / RNA-Binding Proteins - physiology / Young Adult