title: Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease.
abstract: Mutations in FOXE3 are associated with both recessive and dominant inheritance of severe anterior ocular malformations and glaucoma. However, functional analyses of putative pathogenic mutations have not been performed. We tested the hypothesis that variations in FOXE3 activity underlie the different modes of inheritance and disease phenotype. In band shift assays, three recessive mutants showed loss-of-function, one retained DNA binding activity, whereas two dominant mutants showed altered activity. All six mutants showed reduced transactivation function compared with wild-type, and modeling the heterozygous state resulted in an intermediate level of activity providing no evidence for dominant negative action. Our in vitro data are consistent with loss-of-function below a dosage sensitive threshold as a mechanism of action for recessive mutations, but indicate an altered mutant protein function rather than a haploinsufficient mechanism for dominant mutations. This study provides the first functional evidence demonstrating that FOXE3 mutations identified in patients impair protein function with differential effects.
authors.affiliation: Developmental Biology and Cancer, Birth Defects Research Centre, UCL Institute of Child Health, London, UK.
authors.forename: Lily
authors.initials: L
authors.lastname: Islam
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Laura
authors.initials: L
authors.lastname: Williamson
authors.forename: Nicola
authors.initials: N
authors.lastname: Lewis
authors.forename: Maria Bitner
authors.initials: MB
authors.lastname: Glindzicz
authors.forename: Ken K
authors.initials: KK
authors.lastname: Nischal
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sowden
mesh_terms: D015785:Eye Diseases, Hereditary / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009154:Mutation
chemical_list: C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors
keywords: FOXE3; anterior segment dysgenesis; aphakia; congenital eye defect; corneal opacity; glaucoma