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Comprehensive phenotypic and functional analysis of dominant and recessiveFOXE3alleles in ocular developmental disorders
- Source :
- Human Molecular Genetics
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
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.
- Subjects :
- Male
AcademicSubjects/SCI01140
0301 basic medicine
Adolescent
genetic structures
Developmental Disabilities
Pedigree chart
Biology
Eye
Microphthalmia
Cataract
03 medical and health sciences
Corneal Opacity
0302 clinical medicine
Cataracts
Genetics
medicine
Humans
Missense mutation
Eye Abnormalities
Sclerocornea
Allele
Child
Molecular Biology
Alleles
Genetics (clinical)
Forkhead Transcription Factors
General Medicine
medicine.disease
Phenotype
eye diseases
Pedigree
030104 developmental biology
Aniridia
Mutation
030221 ophthalmology & optometry
Female
General Article
sense organs
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....5cfec97bce07366523b957757eb67830