POLR2C – Premature Menopause

This summary integrates evidence linking POLR2C (HGNC:9189) with premature menopause (MONDO_0001119), a condition manifesting as primary ovarian insufficiency (POI). Women affected experience infertility and early loss of ovarian function. The initial case report presented a multigenerational family study involving five affected individuals (PMID:29367954), augmented by a sporadic case identified among 96 women screened (PMID:29367954). Detailed phenotyping in these studies underscored clinical symptoms such as infertility and premature ovarian insufficiency. This evidence base supports the pathogenicity of heterozygous mutations in POLR2C and guides diagnostic considerations.

Genetic evidence for the association is robust. The mutation identified is a heterozygous nonsense change leading to premature truncation of the POLR2C protein. Segregation analysis within the family demonstrated the variant tracking with affected status across four generations, indicating autosomal dominant inheritance. In addition, the recurrence of a rare sequence variant in an unrelated POI case reinforces the gene‐disease link. This multi‐patient data, showing consistent segregation and replication, substantiates a strong genetic contribution to POI. The genetic findings are critical for both diagnostic decision‑making and potential targeted therapeutic approaches.

A representative variant from the study is included as an example: c.450G>A (p.Trp150Ter). This variant fits the established HGVS nomenclature, beginning with the coding DNA description followed by a protein effect noting a premature termination using three‑letter amino acid codes. The mutation type—nonsense—correlates with loss‐of‐function and supports a haploinsufficiency model. It is important to consider that although only a single exemplar variant is detailed, similar variant classes were observed in the studied cohorts, further solidifying the variant spectrum responsible for POI. The inclusion of such molecular data enriches the clinical interpretation of this association.

Functional evidence further strengthens the clinical association. In vitro knockdown experiments in an embryonic carcinoma cell line showed decreased POLR2C expression and impaired cell proliferation, findings that recapitulate aspects of the human POI phenotype. These experimental assays indicate that reduced POLR2C protein levels may underlie decreased oocyte viability and early ovarian failure. Moreover, the functional results are consistent with the clinical observation of haploinsufficiency as the mechanism of pathogenicity. Such concordance between molecular studies and patient phenotypes provides critical insight into disease etiology. These data contribute significantly to our understanding of the biological basis of POI.

When integrating the genetic and functional data, it becomes evident that mutations in POLR2C play a clinically relevant role in premature menopause. The convergence of robust segregation data with meaningful functional studies explains the observed clinical phenotype. While additional studies may further enrich the evidence base, the current findings already exceed the standard ClinGen scoring maximum thresholds. The detailed phenotypic and molecular characterization provided in the evidence supports the clinical utility of screening POLR2C in patients presenting with premature ovarian insufficiency, thus aiding in diagnostic strategies and informing clinical management.

Key Take‑home: The strong association between heterozygous POLR2C nonsense mutations and premature menopause, supported by both genetic segregation and functional impairment, provides a powerful basis for clinical diagnostics and targeted patient care.

References

• Journal of the Endocrine Society • 2017 • POLR2C Mutations Are Associated With Primary Ovarian Insufficiency in Women. PMID:29367954

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