FOXE3 – Anterior segment dysgenesis

FOXE3 encodes a forkhead transcription factor essential for lens and anterior segment development. Pathogenic variants in FOXE3 cause a spectrum of anterior segment dysgenesis (ASD), ranging from microcornea and aphakia to Peters anomaly. Both autosomal recessive loss-of-function and autosomal dominant non-stop extension variants have been reported, underscoring dosage sensitivity of FOXE3 in ocular morphogenesis.

Autosomal dominant FOXE3 variants include a novel non-stop mutation c.959G>T (p.Ter320Leu) extending the C-terminus by 72 amino acids, which co-segregated with variable ASD in 11 affected relatives over 30 years of a Newfoundland pedigree (PMID:21150893). Autosomal recessive inheritance is exemplified by homozygous missense c.289A>G (p.Ile97Val) segregating with ASD in a consanguineous Pakistani family (PMID:32976546). Exome sequencing of 24 South Florida ASD families identified FOXE3 variants in 1 family, further supporting its role in ASD (PMID:32224865).

A comprehensive mutation update documented 52 FOXE3 variants, of which 33 are unique causal alleles, including truncating, missense, frameshift and non-stop extension variants in 16 new families with ASD and related ocular defects (PMID:29314435). A recent study of 16 additional families detailed a broad phenotypic range for recessive alleles (corneal opacity in 90%, aphakia in 83%, microphthalmia in 80%) and dominant extension alleles causing cataract with variable anterior segment anomalies (PMID:34046667).

Segregation analysis includes 11 affected relatives in the dominant non-stop family and co-segregation in recessive pedigrees, meeting criteria for strong genetic evidence. The variant spectrum encompasses missense, truncating, extension and frameshift alleles, with both AD and AR modes.

Functional assays demonstrate that recessive FOXE3 mutants lose DNA-binding or transactivation activity, while dominant extension alleles exert altered function without clear dominant-negative effects, consistent with a threshold model of haploinsufficiency (PMID:25504734). A zebrafish foxe3 indel model recapitulates lens defects and microphthalmia with dysregulation of lens-enriched genes, confirming conserved developmental roles (PMID:29713869).

Integrated genetic and experimental data classify the FOXE3–ASD association as Strong. FOXE3 testing is clinically actionable for diagnosis of ASD and related anterior segment malformations.

References

• European Journal of Human Genetics • 2011 • A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly PMID:21150893
• PLoS One • 2020 • Pathogenic variants of AIPL1, MERTK, GUCY2D, and FOXE3 in Pakistani families with clinically heterogeneous eye diseases PMID:32976546
• Genes • 2020 • Spectrum of Genetic Variants Associated with Anterior Segment Dysgenesis in South Florida PMID:32224865
• Human Mutation • 2018 • Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects PMID:29314435
• Human Molecular Genetics • 2021 • Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders PMID:34046667
• Human Mutation • 2015 • Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease PMID:25504734
• Human Genetics • 2018 • A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans PMID:29713869

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