FOXE3 – Cataract

The forkhead transcription factor FOXE3 is essential for lens epithelial proliferation and differentiation. Heterozygous and homozygous FOXE3 variants have been linked to a spectrum of congenital lens defects, notably isolated cerulean cataract, early-onset adult nuclear and cortical cataract, and broader anterior segment anomalies, establishing its role in both syndromic and nonsyndromic cataract (PMID:19708017).

Two unrelated families harboring novel heterozygous FOXE3 mutations segregate dominantly with isolated cataract phenotypes, including cerulean and adult nuclear–cortical subtypes, identified through targeted screening of 236 individuals with developmental eye anomalies (PMID:19708017). Further large-scale variant curation documented 52 FOXE3 alleles across diverse ocular defects, with 33 unique causal mutations implicated in cataract and allied phenotypes (PMID:29314435).

The FOXE3 variant spectrum includes missense substitutions (e.g., c.244A>G (p.Met82Val)), non-stop extension alleles (c.959G>T (p.Ter320Leu)), frameshifts, and forkhead-domain disruptions. Both dominant extension and recessive missense/truncating variants are represented among cataract cases, underscoring allelic heterogeneity (PMID:29314435; PMID:34046667).

Functional analyses reveal that recessive FOXE3 missense mutants exhibit loss of DNA-binding and reduced transcriptional activation, while dominant extension variants demonstrate altered activity with intermediate transactivation levels rather than classical dominant-negative effects (PMID:25504734).

A zebrafish foxe3 indel model recapitulates lens opacification and microphthalmia, with RNA-seq demonstrating dysregulation of cataract-associated genes (cryba2a, cryba1l1, mipa, hsf4), confirming conserved pathways in vertebrate lens transparency (PMID:29713869).

Collectively, genetic and experimental data support a moderate clinical validity for FOXE3 in isolated and syndromic cataract via haploinsufficiency and altered transcription factor function. Inclusion of FOXE3 in diagnostic gene panels is recommended for patients with familial or early-onset cataract.

References

• Human mutation • 2009 • Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. PMID:19708017
• Human mutation • 2018 • Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects. PMID:29314435
• Human mutation • 2015 • Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease. PMID:25504734
• Human molecular genetics • 2021 • Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders. PMID:34046667
• 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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