Background
Ovarian development consists of a series of elaborate developmental processes, including primordial germ cell migration and development, meiosis, and folliculogenesis. The ovarian reserve is related to the number and quality of the remaining oocytes. As such, diminished ovarian reserve (DOR) is used to describe women of reproductive age with regular menstruation cycles whose response to ovarian stimulation or reproductive capacity is less than that of women of comparable age. DOR can be identified based on an abnormal ovarian reserve test (antral follicular count < 5–7 follicles or anti-Mullerian hormone < 0.5–1.1 ng/mL) [
1]. DOR is different from premature ovarian insufficiency (POI), which is characterized by at least 4 months of amenorrhea or oligomenorrhea, elevated follicle-stimulating hormone (FSH) levels (> 25 IU/L), and low estradiol. The prevalence of POI is ~ 1% in the general population [
2]. Several factors, including chromosomal abnormalities, Fragile X premutations, point mutations, autoimmune disorders, and medical or surgical interventions, contribute to the onset of POI. However, the causes of POI for most women remain unclear, although unexplored genetic factors may partially explain some POI cases. POI and DOR share a common pathogenesis and are both related to abnormal ovarian reserves. We thus hypothesize that DOR may represent an early stage and partial manifestation of POI.
From a genetic point of view, POI is a heterogeneous disease [
3]. The pathogenic molecular mechanism of POI has been thought involve mutations in genes involved in several developmental processes, including primordial germ cell survival [
4], DNA repair and meiotic recombination [
5‐
12], oocyte transcription and translational control during folliculogenesis [
13‐
20], granulosa cell development [
21‐
25], and oocyte mitochondrial function [
26,
27].
EIF4ENIF1, or eukaryotic translation initiation factor 4E nuclear import factor 1, is a nucleocytoplasmic shuttle protein that is enriched in P-bodies for transport of the translation initiation factor eIF4E. In addition, EIF4ENIF1 can competitively prevent the productive binding of eIF4E to eIF4G, thereby reducing protein synthesis by regulating ribosomal delays through interfering with the interaction between eIF4E and eIF4G [
28]. EIF4ENIF1 can thus control access of the 5′ cap of specific mRNAs by ribosomes and mediate translational repression [
29,
30]. Previous studies have shown that EIF4ENIF1 is a part of a large CPEB (Cytoplasmic Polyadenylation Element Binding) translation inhibitor RNP (RiboNucleoProtein) complex in
Xenopus laevis oocytes [
31]. In mouse oocytes, EIF4ENIF1 is essential for breakdown of the nuclear envelope and the resumption of meiosis [
32]. Moreover, in a large French-Canadian family [
20], seven women affected with POI possessed a heterozygous premature stop codon (Ser429*) in
EIF4ENIF1 that was not present in the unaffected members, suggesting a dominant mode of inheritance of POI-causing
EIF4ENIF1 mutations [
20].
EIF4ENIF1 is therefore a good candidate gene for investigation to determine its role in POI and ovarian reserve abnormalities.
In this study, we recruited a family in which the proband was diagnosed with DOR and whose mother was a POI patient. We then used whole-exome sequencing to dissect the genetic causes underlying DOR in this family.
Discussion
In this study, we identified an EIF4ENIF1 heterozygous variant in a patient with DOR using WES. Moreover, we found that this patient inherited the variant from her mother, who suffers from POI. Bioinformatics analysis suggests that the variant c.2525A > C;p.Q842P may be a pathogenic allele. Additionally, secondary structure modeling suggests that Q842P may change the original α-helix structure.
The
EIF4ENIF1 mutation found in this study is a heterozygous mutation, in line with its dominant inheritance. The genetic mode of inheritance of POI in this study is consistent with that described in the previously published literature [
20]. Two possible mechanisms can be used to explain the presence of this mutation: haploinsufficiency or the dominant-negative effect. However, previously published studies [
20] indicate that the haploinsufficiency mechanism is more likely since these studies found a premature stop codon (p.Ser429*) in a variant of
EIF4ENIF1 while our study identified a point mutation (p.Q842P) in
EIF4ENIF1. Since we have not done the relevant functional experiments, we cannot determine whether the effect of this point mutation completely eliminates protein function. However, the haploinsufficiency mechanism is more likely the cause of the effects of heterozygous
EIF4ENIF1 mutations since the EIF4ENIF1 protein has not been reported to function as a dimer. In general, when a protein can function as a dimer, the mutation found in that protein will have a dominant negative effect. EIF4ENIF1 inhibits protein translation by binding to EIF4E [
35], decreases in levels of EIF4ENIF1 lead to partial decreases in EIF4E inhibition, which may result in increased protein translation and enhanced mRNA stability.
Conclusions
In conclusion, our study identified a rare mutation of the EIF4ENIF1 gene in a family exhibiting DOR and POI. Online bioinformatics analysis suggests that this mutation is a pathogenic mutation. Moreover, secondary structural biology prediction analysis suggests that this mutation either causes the destruction of the α-helical structure around the mutation site or a reduction in α-helix length. This mutation is the second novel mutation of EIF4ENIF1, identified in POI patients. This study therefore provides new information on POI genetics and a novel gene locus for use in genetic counseling for POI and related diseases.
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