FOXL2 – Premature Menopause

FOXL2 encodes a forkhead transcription factor critical for ovarian development. Heterozygous variants in FOXL2 cause autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome type I, in which eyelid malformations are coupled with premature ovarian failure (POF), also known as premature menopause. FOXL2 expression is first detected in granulosa cells of developing follicles, and its disruption leads to ovarian insufficiency often before age 40 (Gene Symbol; Premature Menopause).

Several case reports describe FOXL2 variants in non-syndromic POF. A de novo missense variant, c.560G>A (p.Gly187Asp), was identified in a woman with isolated POF and shown to reduce transactivation of an ovarian reporter promoter (PMID:19429596). Two additional non-syndromic POF patients harbored coding changes c.663_692del (p.Ala225_Ala234del) and c.772T>A (p.Tyr258Asn), absent in 200 controls (PMID:12149404). These findings support FOXL2 involvement beyond its canonical syndromic presentation.

In BPES type I pedigrees, FOXL2 truncating variants segregate with POF. A heterozygous thymidine deletion, c.627delT (p.Ser211HisfsTer?), was found in a sporadic BPES case with hypergonadotropic hypogonadism (PMID:19969293). In an AD family, the c.988_989insG (p.Ala330GlyfsTer?) indel co-segregated with POF in three affected women, confirming autosomal dominant inheritance and segregation in multiple relatives.

However, large POF cohorts show a low yield of FOXL2 mutations. Sequencing of 120 idiopathic POF patients revealed no FOXL2 coding variants (PMID:15181179), and analysis of 118 Chinese POF cases identified only a common 30 bp polyalanine duplication in one BPES patient (PMID:20222838). This suggests FOXL2 variants account for a minority of non-syndromic POF.

Functional assays demonstrate that FOXL2 variants impair ovarian gene regulation by haploinsufficiency or dominant-negative effects. The p.Gly187Asp mutant shows normal localization but reduced transactivation of an ovarian promoter (PMID:19429596). Truncated FOXL2 proteins lacking the polyalanine tract aggregate intranuclearly and sequester wild-type protein, further diminishing transcriptional repression of targets such as STAR (PMID:16219626).

Overall, the clinical validity of FOXL2 in premature menopause is Moderate. Multiple unrelated POF probands (n = 5) with functionally deleterious FOXL2 variants and segregation in AD families, combined with concordant in vitro evidence, support the association. Yet population screens indicate FOXL2 alterations are rare in non-syndromic POF. FOXL2 testing is recommended in POF patients with eyelid anomalies or family history of BPES, with functional assays guiding variant interpretation.

Key Take-home: FOXL2 haploinsufficiency underlies syndromic and, less commonly, non-syndromic premature menopause, and targeted FOXL2 analysis informs diagnosis and reproductive counseling.

References

• Journal of medical genetics • 2009 • Functional evidence implicating FOXL2 in non-syndromic premature ovarian failure and in the regulation of the transcription factor OSR2 PMID:19429596
• Molecular human reproduction • 2002 • Identification of novel mutations in FOXL2 associated with premature ovarian failure PMID:12149404
• Fertility and sterility • 2010 • A new FOXL2 gene mutation in a woman with premature ovarian failure and sporadic blepharophimosis-ptosis-epicanthus inversus syndrome PMID:19969293
• Molecular human reproduction • 2004 • Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure PMID:15181179
• Gynecological endocrinology • 2010 • Mutation analysis of FOXL2 gene in Chinese patients with premature ovarian failure PMID:20222838
• Human molecular genetics • 2005 • Deletions in the polyAlanine-containing transcription factor FOXL2 lead to intranuclear aggregation PMID:16219626

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