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XPNPEP2 and Premature Menopause

XPNPEP2 encodes aminopeptidase P, an enzyme involved in peptide processing, and has been evaluated as a candidate gene in premature menopause (PMID:34095689, PMID:38649916). Two independent next generation sequencing studies in primary ovarian insufficiency (POI) cohorts—one comprising 269 patients and another 48 patients—included XPNPEP2 in their gene panels, but did not report gene‐specific pathogenic variants or segregation data. This lack of detailed variant evidence and familial segregation restricts the strength of the genetic association.

Functional studies, however, lend additional support to a potential role for XPNPEP2 in ovarian biology. Expression analysis in multiple human tissues revealed that aminopeptidase P isoforms, including that encoded by XPNPEP2, are broadly expressed and might influence peptide regulation relevant to ovarian function (PMID:15708373). Moreover, a molecular assay investigating XPNPEP2 polymorphisms in clinical settings demonstrated that certain allelic variants can affect enzyme activity (PMID:23276181). Although these functional data are supportive, direct evidence linking XPNPEP2 variants to premature menopause is limited. Inheritance is presumed to be autosomal dominant given its inclusion in heterozygous screening panels for POI. Overall, the evidence presently supports a limited gene–disease association. Key take‑home message: While preliminary genetic and functional data suggest XPNPEP2 may contribute to premature menopause, further studies are necessary to validate its diagnostic and therapeutic utility.

References

  • Journal of the Endocrine Society • 2021 • Next Generation Sequencing Should Be Proposed to Every Woman With "Idiopathic" Primary Ovarian Insufficiency PMID:34095689
  • Archives of pathology & laboratory medicine • 2013 • The development of a novel molecular assay examining the role of aminopeptidase P polymorphisms in acute hypotensive transfusion reactions PMID:38649916
  • Archives of biochemistry and biophysics • 2005 • Aminopeptidase P isozyme expression in human tissues and peripheral blood mononuclear cell fractions PMID:15708373

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Candidate gene data from two POI studies (269 patients [PMID:34095689], 48 patients [PMID:38649916]) lack specific segregation or detailed variant evidence for XPNPEP2.

Genetic Evidence

Limited

XPNPEP2 was included in multi‐gene NGS panels for POI, but no definitive pathogenic coding variant has been reported, limiting the direct genetic proof.

Functional Evidence

Moderate

Functional assays demonstrate broad tissue expression and suggest that XPNPEP2 influences peptide regulation, a process that may affect ovarian function (PMID:15708373, PMID:23276181).