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GPR3 and Premature Menopause

Evidence for the association between GPR3 and premature menopause remains limited. Several independent studies in cohorts of women with premature ovarian failure or insufficiency (e.g. 82 women screened in one study (PMID:17953967), and 100 Chinese patients in another (PMID:20158988)) failed to identify significant coding perturbations in GPR3. However, a recent case series reported two heterozygous missense variants, including the variant c.772G>A (p.Ala258Thr) identified in one proband, suggesting a potential albeit rare genetic contribution to the phenotype (PMID:37919810).

Functional studies further support a potential mechanism whereby GPR3 regulates oocyte meiotic arrest via constitutive cAMP signaling. In vitro experiments demonstrated that alterations in GPR3 surface localization and cAMP production, modulated by overexpression of GRK2 and β‑arrestin‑2, may disrupt the maintenance of meiotic arrest (PMID:23826079). While these experimental findings provide mechanistic insight, the overall genetic evidence for GPR3 in premature menopause is limited. The integration of negative large-scale sequencing studies with isolated case reports underscores the need for further research to ascertain the gene’s clinical utility in diagnostic decision‑making.

References

  • Fertility and Sterility • 2008 • Oocyte-specific G-protein-coupled receptor 3 (GPR3): no perturbations found in 82 women with premature ovarian failure PMID:17953967
  • Reproductive Biomedicine Online • 2010 • GPR3 may not be a potential candidate gene for premature ovarian failure PMID:20158988
  • Journal of the Endocrine Society • 2021 • Next Generation Sequencing Should Be Proposed to Every Woman With "Idiopathic" Primary Ovarian Insufficiency PMID:34095689
  • Journal of Ovarian Research • 2023 • Rare variants in GPR3 in POI patients: a case series with review of literature PMID:37919810
  • PLOS ONE • 2013 • Regulation of Constitutive GPR3 Signaling and Surface Localization by GRK2 and β‑arrestin‑2 Overexpression in HEK293 Cells PMID:23826079

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Only 2 probands with heterozygous missense variants were reported (PMID:37919810) amid several larger studies that failed to detect significant coding changes.

Genetic Evidence

Limited

Genetic evidence is restricted to a single case series with two heterozygous variants, while additional screening in multiple cohorts consistently returned negative findings.

Functional Evidence

Moderate

In vitro assays demonstrate that modulation of GPR3 localization and cAMP signaling by GRK2/β‑arrestin‑2 aligns with a functional mechanism essential for oocyte meiotic arrest (PMID:23826079).