Novel mutations in TRIP13 lead to female infertility with oocyte maturation arrest.

Oocyte maturation arrest (OMA) refers to a rare clinical phenomenon of oocyte maturation disorder caused by abnormal meiosis, which is also one of the primary causes of female infertility. The clinical manifestations of these patients are often characterized with failure to obtain mature oocytes after repeated ovulation stimulation and/or induced in vitro maturation. To date, mutations in PATL2, TUBB8 and TRIP13 have been demonstrated to be associated with OMA, but studies on the genetic-based factors and mechanisms of OMA are still incomplete. In this study, peripheral blood from 35 primary infertile women characterized with recurrent OMA during assisted reproductive technology (ART) were subjected to whole-exome sequencing (WES). By using Sanger sequencing and co-segregated analysis, we identified four pathogenic variants in TRIP13. Proband 1 had a homozygous missense mutation of c.859A>G appeared on the 9th exon, which resulted in substitution of Ile287 to valine (p.Ile287Val); proband 2 had a homozygous missense mutation of c.77A>G on the 1st exon, which resulted in substitution of His26 to arginine (p.His26Arg); and proband 3 had compound heterozygous mutations of c.409G>A and c.1150A>G on the 4th and 12th exon, which resulted in the substitutions of Asp137 to asparagine (p.Asp137Asn) and Ser384 to glycine (p.Ser384Gly) in the encoded protein respectively. Three of these mutations have not been reported previously. Further, transfection of plasmids harboring the respective mutated TRIP13 in HeLa cells resulted in changes in TRIP13 expression and abnormal cell proliferation as demonstrated by western blotting and cell proliferation assay respectively. This study further summarizes the TRIP13 mutations reported previously and expands the mutation spectrum of TRIP13 pathogenic variants, thereby providing a valuable reference for further research on the pathogenic mechanism of OMA associated with TRIP13 mutations.

Selective Translation of Maternal mRNA by eIF4E1B Controls Oocyte to Embryo Transition.

Maternal messenger ribonucleic acids (mRNAs) are driven by a highly orchestrated scheme of recruitment to polysomes and translational activation. However, selecting and regulating individual mRNAs for the translation from a competitive pool of mRNAs are little-known processes. This research shows that the maternal eukaryotic translation initiation factor 4e1b (Eif4e1b) expresses during the oocyte-to-embryo transition (OET), and maternal deletion of Eif4e1b leads to multiple defects concerning oogenesis and embryonic developmental competence during OET. The linear amplification of complementary deoxyribonucleic acid (cDNA) ends, and sequencing (LACE-seq) is used to identify the distinct subset of mRNA and its CG-rich binding sites within the 5' untranslated region (UTR) targeted by eIF4E1B. The proteomics analyses indicate that eIF4E1B-specific bound genes show stronger downregulation at the protein level, which further verify a group of proteins that plays a crucial role in oocyte maturation and embryonic developmental competence is insufficiently synthesized in Eif4e1b-cKO oocytes during OET. Moreover, the biochemical results in vitro are combined to further confirm the maternal-specific translation activation model assembled by eIF4E1B and 3'UTR-associated mRNA binding proteins. The findings demonstrate the indispensability of eIF4E1B for selective translation activation in mammalian oocytes and provide a potential network regulated by eIF4E1B in OET.