EIF4ENIF1 and Premature Menopause

Multiple independent studies have demonstrated that rare deleterious variants in EIF4ENIF1 are associated with premature menopause. In an initial family‐based study, a heterozygous stop codon variant (resulting in p.Ser429Ter) segregated with primary ovarian insufficiency in a family with 9 affected women spanning 3 generations (PMID:23902945). This finding supports a genetically dominant mechanism, as affected individuals clearly exhibit the phenotype while unaffected family members do not.

Subsequent multi-patient investigations have identified additional variants in EIF4ENIF1, including the missense variant c.2861G>C (p.Gly954Ala), in sporadic cases of premature ovarian insufficiency (PMID:36030004). These studies further reinforced the genetic evidence by documenting variant rarity in the general population and by demonstrating consistent segregation patterns in affected patients.

Genetic evidence is bolstered by functional assessments showing that EIF4ENIF1 variants impair the regulation of mRNA translation. In vitro experiments revealed that mutated proteins exhibit reduced mRNA and protein expression levels and fail to adequately repress translation, suggesting a mechanistic link between the variant and ovarian dysfunction (PMID:38604507). The concordance between genetic and functional data strengthens the clinical validity of this association.

Beyond direct genetic and experimental results, evaluations from screening panels in heterogeneous patient cohorts highlight that EIF4ENIF1 mutations, alongside other candidate genes, contribute to the complex genetic architecture of premature ovarian insufficiency. The diversity of variant types—including truncating and missense changes—adds further support to the role of EIF4ENIF1 in the disease etiology.

In summary, the integration of family segregation data, case series, and robust functional assays provides a coherent narrative that supports a dominant pathogenic mechanism for EIF4ENIF1 in premature menopause. This body of evidence not only bolsters diagnostic decision‑making but also underscores the gene’s utility in the stratification of patient care and future translational research.

Key Take‑home Sentence: Screening for EIF4ENIF1 variants offers a valuable tool in early diagnosis and genetic counseling for women at risk of premature ovarian insufficiency.

References

• The Journal of clinical endocrinology and metabolism • 2013 • Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency PMID:23902945
• European journal of medical genetics • 2022 • EIF4ENIF1 variants in two patients with non‑syndromic premature ovarian insufficiency PMID:36030004
• Gene • 2024 • POI‑associated EIF4ENIF1 mutations exhibit impaired translation regulation abilities PMID:38604507

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