Comprehensive phenotypic and functional analysis of dominant and recessiveFOXE3alleles in ocular developmental disorders

Abstract

The forkhead transcription factor FOXE3 is critical for vertebrate eye development. Recessive and dominant variants cause human ocular disease but the full range of phenotypes and mechanisms of action for the two classes of variants are unknown. We identified FOXE3 variants in individuals with congenital eye malformations and carried out in vitro functional analysis on selected alleles. Sixteen new recessive and dominant families, including six novel variants, were identified. Analysis of new and previously reported genetic and clinical data demonstrated a broad phenotypic range with an overlap between recessive and dominant disease. Most families with recessive alleles, composed of truncating and forkhead-domain missense variants, had severe corneal opacity (90%; sclerocornea in 47%), aphakia (83%), and microphthalmia (80%), but some had milder features including isolated cataract. The phenotype was most variable for recessive missense variants, suggesting that the functional consequences may be highly dependent on the type of amino acid substitution and its position. When assessed, aniridia or iris hypoplasia were noted in 89% and optic nerve anomalies in 60% of recessive cases, indicating that these defects are also common and may be underrecognized. In dominant pedigrees, caused by extension variants, normal eye size (96%), cataracts (99%), and variable anterior segment anomalies were seen in most, but some individuals had microphthalmia, aphakia, or sclerocornea, more typical of recessive disease. Functional studies identified variable effects on the protein stability, DNA binding, nuclear localization and transcriptional activity for recessive FOXE3 variants, whereas dominant alleles showed severe impairment in all areas and dominant-negative characteristics.

First evidence of SOX2 mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

“…Three individuals ( P64 , P70 , P90 ) had variants in the FOXE3 gene (3/95 = 3%; 3/34 = 9% of positive cases), resulting in the severe ocular phenotype of complex microphthalmia and PA. P64 was one of two siblings, previously reported with a homozygous missense variant (c.232G>A p.Ala78Thr) 13 . Surprisingly, patient P70 carried a monoallelic c.960A>C stop‐loss variant, which is usually associated with milder ocular anomalies of dominant inheritance 13,32 . An undetected modifying factor in cis or in trans of the stop‐loss variant might explain the severity of his phenotype.…”

“…13 Surprisingly, patient P70 carried a monoallelic c.960A>C stop-loss variant, which is usually associated with milder ocular anomalies of dominant inheritance. 13,32 An undetected modifying factor in cis or in trans of the stop-loss variant might explain the severity of his phenotype.…”

Status of Visual Impairment among Children with Special Needs in Rural China

“…FOXE3 is usually associated with developmental anterior ocular anomalies, such as sclerocornea and microphthalmia [21]. One study also reported FOXE3 in intellectual disability and autism, but the underlying causes remained unknown [22]. CRB1 mutations are associated with several retinopathies, such as Leber congenital amaurosis and retinitis pigmentosa.…”

Genomic instability and eye diseases

“…Genetic screening is a useful tool for diagnosing these diseases. Sclerocornea-related genes that have been reported include FOXE3 , 59 , 60 BMP4 , 61 SOX2 , 62 RAX , 63 PAX6 , 64 NDP 64 and RAD21 . 65 These genes play critical roles in eye development and patients carrying mutations usually suffer from malformation of the eye.…”