Biallelic variants in ZFP36L2 cause female infertility characterised by recurrent preimplantation embryo arrest

Abstract

BackgroundRecurrent preimplantation embryo developmental arrest (RPEA) is the most common cause of assisted reproductive technology treatment failure associated with identified genetic abnormalities. Variants in known maternal genes can only account for 20%–30% of these cases. The underlying genetic causes for the other affected individuals remain unknown.MethodsWhole exome sequencing was performed for 100 independent infertile females that experienced RPEA. Functional characterisations of the identified candidate disease-causative variants were validated by Sanger sequencing, bioinformatics and in vitro functional analyses, and single-cell RNA sequencing of zygotes.ResultsBiallelic variants in ZFP36L2 were associated with RPEA and the recurrent variant (p.Ser308_Ser310del) prevented maternal mRNA decay in zygotes and HeLa cells.ConclusionThese findings emphasise the relevance of the relationship between maternal mRNA decay and human preimplantation embryo development and highlight a novel gene potentially responsible for RPEA, which may facilitate genetic diagnoses.

A novel homozygous variant in ZFP36L2 cause female infertility due to oocyte maturation defect

“…However, the deletion of N‐terminal 29 amino acids (ΔN‐ZFP36L2), which did not impair tandem zinc finger domain, only led to female infertility characterized by all embryos arrested at 2‐cell stage 12 . Previous study has suggested that affected women harboring bi‐allelic ZFP36L2 variants (p.308_310del and p.Ser308Ala) in the junction region of two domains displayed early embryonic arrest 9 . In this study, the pathogenic variant identified was a truncation of three amino acids in the nondefined region, leading to defective oocytes, such as immature oocytes, ZP‐free oocytes, degenerated oocytes, nonfertilized oocytes, and arrested embryo (Table S1).…”

“…12 Previous study has suggested that affected women harboring bi-allelic ZFP36L2 variants (p.308_310del and p.Ser308Ala) in the junction region of two domains displayed early embryonic arrest. 9 In this study, the pathogenic variant identified was a truncation of three amino acids in the nondefined region, leading to defective oocytes, such as immature oocytes, ZP-free oocytes, degenerated oocytes, nonfertilized oocytes, and arrested embryo (Table S1). And the mutated site is not conserved between ZFP36L2 and its homolog ZFP36 which is required for mediating reproduction-related mRNA decay.…”

“…8 Previously, it has been reported that bi-allelic variants in ZFP36L2 (c.922_930del, p.308_310del; c.922T>G, p.Ser308Ala) cause early embryonic arrest and female infertility. 9 However, only a limited number of families with early embryonic arrest have been detected with ZFP36L2 variants and those affected individuals exhibited a different phenotype to oocyte-specific Zfp36l2 conditional knockout mice. Thus, additional research is still needed to identify novel ZFP36L2 variants and determine whether the variants are involved in other infertile phenotypes.…”

“…Oocyte‐specific Zfp36l2 conditional knockout in mice causes oocyte maturation defect and fertilization failure 8 . Previously, it has been reported that bi‐allelic variants in ZFP36L2 (c.922_930del, p.308_310del; c.922T>G, p.Ser308Ala) cause early embryonic arrest and female infertility 9 . However, only a limited number of families with early embryonic arrest have been detected with ZFP36L2 variants and those affected individuals exhibited a different phenotype to oocyte‐specific Zfp36l2 conditional knockout mice.…”

Epigenetic reprogramming during the maternal‐to‐zygotic transition

“…Moreover, ZFP36L2‐CCR4‐NOT CNOT6L guided maternal mRNA decay has been demonstrated to be necessary for accurate MZT in human. The biallelic mutation in Zfp36l2 perturbs the removal of massive ARE‐containing transcripts in human zygotes and is potentially responsible for the occurrence recurrent preimplantation embryo developmental arrest 191 . Altogether, the stage‐specific maternal mRNAs decay guided by these different modes of CCR4‐NOT recruitment is conserved in mammals.…”