PSMC3IP and Premature Menopause

Multiple independent studies have reported biallelic variants in PSMC3IP in patients presenting with features of premature menopause. In a consanguineous family, four sisters with primary ovarian insufficiency and one brother with azoospermia were found to carry a homozygous stop‐gain mutation in PSMC3IP, indicating a strong association with reproductive dysfunction (PMID:29240891). Additional case reports have documented compound heterozygous and homozygous mutations in patients with secondary amenorrhea and delayed puberty, reinforcing the role of this gene in ovarian dysgenesis (PMID:34878148; PMID:35352317).

The inheritance pattern observed is autosomal recessive, with segregation analyses indicating that multiple affected relatives in these families carry the deleterious variants. For instance, the consanguineous Yemeni family showed segregation of the homozygous stop‐gain variant, c.489C>G (p.Tyr163Ter), among affected individuals (PMID:29240891). Such segregation of variants across families supports the pathogenicity of PSMC3IP in premature menopause.

Genetic evidence from these case reports includes different classes of variants such as stop‐gain and missense mutations, with at least one valid HGVS variant, c.489C>G (p.Tyr163Ter), being consistently reported. Although some studies have also suggested that additional variants in PSMC3IP may contribute to the broader phenotypic spectrum of ovarian insufficiency, the overall genetic data support a moderate level of evidence for gene–disease association, with several independent families demonstrating similar reproductive phenotypes (PMID:29240891; PMID:34878148).

Functional studies indicate that PSMC3IP plays a critical role in meiotic homologous recombination and DNA repair—a process essential for proper ovarian development. In vitro assays and related studies in cellular models suggest that deficient PSMC3IP activity can impair these pathways, providing a mechanistic link to ovarian dysgenesis (PMID:23946869). Although direct in vivo evidence in reproductive tissues is limited, the experimental data resonate with the clinical observations.

Notably, there is conflicting evidence in the literature; for example, a Swedish cohort study of women with primary ovarian insufficiency failed to identify pathogenic PSMC3IP mutations (PMID:24481226). This discrepancy underscores the possibility of genetic heterogeneity in premature menopause and suggests that while PSMC3IP mutations are pathogenic in certain populations, they may account for only a subset of cases.

In summary, the aggregate genetic and experimental evidence establishes a moderate level of support for an association between biallelic variations in PSMC3IP and premature menopause. Despite some conflicting findings, the consistent phenotype–genotype correlations observed in multiple independent families support the clinical utility of including PSMC3IP in diagnostic panels for ovarian insufficiency.

Key Take‑Home Message: PSMC3IP mutations, acting through impaired meiotic recombination and DNA repair, represent a significant genetic factor in premature menopause and should be considered in the genetic evaluation of reproductive disorders.

References

• The Journal of clinical endocrinology and metabolism • 2018 • Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation PMID:29240891
• Molecular medicine reports • 2022 • Two novel biallelic mutations in PSMC3IP in a patient affected by premature ovarian insufficiency PMID:34878148
• Journal of assisted reproduction and genetics • 2022 • Biallelic mutations in PSMC3IP are associated with secondary amenorrhea: expanding the spectrum of premature ovarian insufficiency PMID:35352317
• Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology • 2014 • No mutations in the PSMC3IP gene identified in a Swedish cohort of women with primary ovarian insufficiency PMID:24481226
• Genes & cancer • 2013 • GT198 Splice Variants Display Dominant-Negative Activities and Are Induced by Inactivating Mutations PMID:23946869

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