POF1B – Premature Menopause

POF1B, an X‑linked gene (POF1B), has been implicated in premature menopause (premature menopause) based on evidence from isolated case reports. In one index case, a patient with premature ovarian failure was found to harbor a heterozygous missense mutation alongside a reciprocal X;autosome translocation, suggesting a potential pathogenic role (PMID:25676666).

Genetic evidence for this association is limited. Several studies have reported the recurrent c.986G>A (p.Arg329Gln) variant as the primary candidate (PMID:25676666; PMID:31026518), yet larger multi‐patient analyses have not consistently supported a significant contribution of POF1B variants to the phenotype (PMID:15459172).

Segregation data are sparse, with no additional affected relatives definitively demonstrating variant co‑segregation in families to date.

Functional studies provide moderate support for a role of POF1B in ovarian function. In cellular models, the POF1B R329Q variant has been shown to disrupt epithelial polarity and impair tight junction assembly through altered actin cytoskeleton dynamics (PMID:21940798).

Despite the functional deficits observed, integration of the genetic and experimental findings yields a limited overall association. Conflicting results from larger genetic cohorts, alongside the small number of independently reported probands, restrict the clinical validity of POF1B as a causative gene for premature menopause (PMID:34707299).

Key take‑home message: While functional impairments linked to the POF1B variant c.986G>A (p.Arg329Gln) underscore a plausible biological mechanism, the limited and conflicting genetic evidence currently restricts its definitive diagnostic utility, warranting further evaluation to solidify its role in premature menopause.

References

• Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation • 2015 • Premature ovarian failure caused by a heterozygous missense mutation in POF1B and a reciprocal translocation PMID:25676666
• Human reproduction (Oxford, England) • 2004 • Mutation analysis of two candidate genes for premature ovarian failure, DACH2 and POF1B PMID:15459172
• Journal of cell science • 2011 • The POF1B candidate gene for premature ovarian failure regulates epithelial polarity PMID:21940798
• European journal of human genetics : EJHG • 2022 • Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes PMID:34707299

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