FOXE3 – Congenital primary aphakia

Congenital primary aphakia (CPA) is a rare developmental disorder characterized by absence of the lens and anterior segment aplasia. In a consanguineous family with three affected siblings, a homozygous FOXE3 nonsense variant, c.145G>T (p.Gly49Ter), segregated with CPA and microphthalmia ([PMID:16826526]), but a separate CPA case presenting microphthalmia, corneal opacity, and anterior segment dysplasia lacked coding mutations in FOXE3, suggesting genetic heterogeneity ([PMID:28805541]).

Zebrafish foxe3 CRISPR/Cas9 indel mutants (c.296_300delTGCAG, p.Val99AlafsTer2) recapitulated lens agenesis and microphthalmia with dysregulated expression of lens-specific genes including cryba2a and cryba1l1 ([PMID:29713869]). Genetic evidence is limited to a single autosomal recessive pedigree with three probands, while functional studies provide moderate support for a loss-of-function mechanism. FOXE3 should be included in diagnostic gene panels for autosomal recessive CPA. Key take-home: Biallelic FOXE3 loss-of-function variants cause congenital primary aphakia.

References

• American journal of human genetics • 2006 • Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. [PMID:16826526]
• Ophthalmic genetics • 2018 • Lack of FOXE3 coding mutation in a case of congenital aphakia. [PMID:28805541]
• 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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