EIF4ENIF1 variants in two patients with non-syndromic premature ovarian insufficiency

Shang, Lingyue; Ren, Shuting; Yang, Xi; Zhang, Feng; Li, Jin; Zhang, Xiaojin; Wu, Yanhua

doi:10.1016/j.ejmg.2022.104597

Cited by 8 publications

(3 citation statements)

References 18 publications

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“…We propose that eIF4ENIF1-mediated repression of eIF4E1b-bound maternal mRNAs in P-bodies is also important for vertebrate oogenesis and embryogenesis. Mutations in eIF4ENIF1 cause infertility in women (Kasippillai et al, 2013 ; Zhao et al, 2019 ; Shang et al, 2022 ), in agreement with both eIF4E1b and eIF4ENIF1 working together to regulate maternal mRNA dormancy.…”

Section: Discussionmentioning

confidence: 76%

eIF4E1b is a non-canonical eIF4E protecting maternal dormant mRNAs

Lorenzo-Orts,

Strobl,

Steinmetz

et al. 2023

EMBO Rep

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Maternal mRNAs are essential for protein synthesis during oogenesis and early embryogenesis. To adapt translation to specific needs during development, maternal mRNAs are translationally repressed by shortening the polyA tails. While mRNA deadenylation is associated with decapping and degradation in somatic cells, maternal mRNAs with short polyA tails are stable. Here we report that the germline-specific eIF4E paralog, eIF4E1b, is essential for zebrafish oogenesis. eIF4E1b localizes to P-bodies in zebrafish embryos and binds to mRNAs with reported short or no polyA tails, including histone mRNAs. Loss of eIF4E1b results in reduced histone mRNA levels in early gonads, consistent with a role in mRNA storage. Using mouse and human eIF4E1Bs (in vitro) and zebrafish eIF4E1b (in vivo), we show that unlike canonical eIF4Es, eIF4E1b does not interact with eIF4G to initiate translation. Instead, eIF4E1b interacts with the translational repressor eIF4ENIF1, which is required for eIF4E1b localization to P-bodies. Our study is consistent with an important role of eIF4E1b in regulating mRNA dormancy and provides new insights into fundamental post-transcriptional regulatory principles governing early vertebrate development.

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Section: Discussionmentioning

confidence: 76%

eIF4E1b is a non-canonical eIF4E protecting maternal dormant mRNAs

Lorenzo-Orts,

Strobl,

Steinmetz

et al. 2023

EMBO Rep

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show abstract

“…Binding of eIF4ENIF1 to eIF4Es has been shown to stabilize deadenylated mRNAs in human cells (Räsch et al, 2020). Mutations in eIF4ENIF1 also cause infertility in women (Kasippillai et al, 2013;Zhao et al, 2019;Shang et al, 2022), in agreement with both eIF4E1B and eIF4ENIF1 working together to promote maternal mRNA dormancy.…”

Section: Discussionmentioning

confidence: 85%

eIF4E1b is a non-canonical eIF4E required for maternal mRNA dormancy

Lorenzo‐Orts

Strobl

Steinmetz

et al. 2023

Preprint

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Maternal mRNAs are essential for protein synthesis during oogenesis and early embryogenesis. To adapt translation to specific needs during development, maternal mRNAs are translationally repressed by shortening the polyA tails. While mRNA deadenylation is associated with decapping and degradation in somatic cells, maternal mRNAs with short polyA tails are stable. Here we report an essential role for the germline-specific paralog of the mRNA cap-binding factor eIF4E, known as eIF4E1b, in the storage and repression of maternal mRNAs with short polyA tails. eIF4E1b binds to the mRNA cap and is targeted to ribonucleoprotein complexes through its direct interaction with eIF4ENIF1/4E-T. In early embryos, eIF4E1b binds to a specific set of translationally repressed mRNAs with short or no polyA tails, such as histone mRNAs, which are translated later on during embryogenesis. Consistent with an important role in maternal mRNA dormancy, mutation of eIF4E1b in zebrafish impairs female germline development. Understanding the mechanism and function of eIF4E1B provides new insights into fundamental post-transcriptional regulatory principles governing early vertebrate development.

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“…In mouse oocytes, knocking‐down Eif4enif1 leads to failure of the oocyte nuclear envelop breakdown and oocyte development arrest (Pfender et al., 2015). To date, five different single‐heterozygous variants in EIF4ENIF1 segregating in an autosomal dominant manner have been found in patients with premature ovarian insufficiency (POI; França et al., 2020; Kasippillai et al., 2013; Shang et al., 2022; Zhao et al., 2019). Four of these variants are missenses predicted by the ACMG (Richards et al., 2015) to be benign/likely benign, and only one is protein‐truncating predicted to be VUS and segregating with the phenotype in a large family.…”

Section: Discussionmentioning

confidence: 99%

A homozygous stop codon in HORMAD2 in a patient with recurrent digynic triploid miscarriage

Liang,

Suresh,

Bareke

et al. 2024

Molec Gen & Gen Med

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BackgroundRecurrent miscarriage (RM) affects 1% to 5% of couples trying to conceive. Despite extensive clinical and laboratory testing, half of the RM cases remain unexplained. We report the genetic analysis of a couple with eight miscarriages and the search for their potential genetic etiology.MethodsShort tandem repeat (STR) markers, single nucleotide polymorphic (SNP) microarray, and human DNA methylation microarray were used to analyze the genotypes of two miscarriages. Exomes sequencing was performed on DNA from the two partners and identified variants were validated by Sanger sequencing.ResultsSTR marker genotyping demonstrated that the two available miscarriages are triploid digynic and resulted from the failure of Meiosis II. SNP microarray analysis revealed an additional Meiosis I abnormality that is the segregation of the two maternal homologous chromosomes in one triploid miscarriage. Whole‐exome sequencing on DNA from the two partners identified candidate variants only in the female partner in two genes with roles in female reproduction, a missense in EIF4ENIF1 (OMIM 607445) and a stop gain in HORMAD2 (OMIM 618842). EIF4ENIF1 is a eukaryotic translation initiation factor 4E nuclear import factor required for the oocyte germinal vesicle breakdown, and HORMAD2 is part of the synaptonemal complex that was hypothesized to act as a checkpoint mechanism to eliminate oocytes with asynapsis during meiotic prophase I in mice.ConclusionWhile both genes may contribute to the phenotype, the Meiosis I abnormalities in the conceptions favor the causal role of HORMAD2 in the etiology of RM in this couple. This report illustrates the importance of comprehensively analyzing the products of conception to guide the search for the genetic causation of RM.

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EIF4ENIF1 variants in two patients with non-syndromic premature ovarian insufficiency

Cited by 8 publications

References 18 publications

eIF4E1b is a non-canonical eIF4E protecting maternal dormant mRNAs

eIF4E1b is a non-canonical eIF4E protecting maternal dormant mRNAs

eIF4E1b is a non-canonical eIF4E required for maternal mRNA dormancy

A homozygous stop codon in HORMAD2 in a patient with recurrent digynic triploid miscarriage

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