FOXL2 – Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant disorder characterized by eyelid malformations and, in type I, premature ovarian failure. The forkhead transcription factor FOXL2 (HGNC:1092) was first implicated in BPES when truncating and polyalanine‐expansion mutations were shown to underlie type I and II phenotypes, respectively (PMID:11468277; PMID:12567411). Truncating mutations upstream of the polyalanine tract typically yield haploinsufficiency and type I BPES, whereas in‐frame polyalanine expansions produce dominant‐negative effects manifesting as isolated eyelid anomalies (type II). Since these initial reports, over 92 distinct intragenic FOXL2 mutations have been catalogued in more than 150 unrelated BPES families, confirming a definitive gene–disease relationship (PMID:18642388).

Inheritance of BPES is autosomal dominant with high penetrance and variable expressivity. Segregation analysis across multiple multi‐generation pedigrees has identified at least 8 additional affected relatives co‐segregating FOXL2 variants, including classic polyalanine duplications and novel frameshifts (PMID:11468277). Case series demonstrate recurrent founder alleles such as the 30-bp in-frame duplication c.672_701dup (p.Ala225_Ala234dup), reported across European, Asian, and African cohorts, and novel indels and missense variants in diverse populations.

The FOXL2 variant spectrum encompasses missense substitutions (n = 13%), nonsense and splice‐site changes (n = 11%), frameshift indels (n = 43%), and polyalanine expansions (n = 30%) (PMID:18642388). The most frequent pathogenic allele is c.672_701dup (p.Ala225_Ala234dup), which expands the polyalanine tract from 14 to 24 residues and recurs via mutational slippage. Representative variant: c.672_701dup (p.Ala225_Ala234dup).

Functional studies reveal that polyalanine expansions and truncated FOXL2 proteins undergo aberrant intranuclear aggregation and cytoplasmic mislocalization, disrupting normal transcriptional activity (PMID:16219626). Missense mutations within the forkhead domain similarly induce mislocalization and loss of transactivation, often via dominant‐negative mechanisms (PMID:18372316). These molecular defects support a model of FOXL2 haploinsufficiency and toxic aggregation underlying BPES pathogenesis.

Beyond eyelid development, FOXL2 regulates ovarian folliculogenesis by repressing promoters of key targets such as the steroidogenic acute regulatory (StAR) and OSR2 genes. Variants such as p.Gly187Asp exhibit normal nuclear localization but reduced transactivation of ovarian promoters, implicating FOXL2 in non-syndromic premature ovarian failure and phenotypic overlap in BPES types (PMID:19429596).

Key take-home: FOXL2 mutations cause a definitive, autosomal dominant BPES phenotype with clear genotype–phenotype correlations for truncating versus expansion alleles, and functional assays offer reliable evidence of pathogenicity. Early genetic testing and personalized counseling are crucial for prognosis, fertility planning, and management.

References

• Human molecular genetics • 2001 • Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families. PMID:11468277
• American journal of medical genetics. Part A • 2003 • FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. PMID:12567411
• Human mutation • 2008 • Identification of 34 novel and 56 known FOXL2 mutations in patients with Blepharophimosis syndrome. PMID:18642388
• Human molecular genetics • 2005 • Deletions in the polyAlanine-containing transcription factor FOXL2 lead to intranuclear aggregation. PMID:16219626
• 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
• Human molecular genetics • 2008 • Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation. PMID:18372316

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