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Lily Islam, Daniel Kelberman, John A. Bradbury, Kanwal K. Nischal, Jane C. Sowden; Functional Analysis of FOXE3 Mutations Causing Dominant and Recessive Anterior Segment Disease. Invest. Ophthalmol. Vis. Sci. 2011;52(14):77.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in the forkhead transcription factor gene FOXE3 are associated with recessive and dominant patterns of inheritance of severe anterior segment developmental anomalies. This study tested the hypothesis that variations in the level of activity of FOXE3 protein underlie the different modes of inheritance and disease phenotypes.
FOXE3 mutation screening was performed by direct sequencing of DNA from families with anterior segment developmental abnormalities including primary aphakia. The transcription factor function of FOXE3 proteins carrying six different pathogenic mutations (2 dominant, 4 recessive) was investigated in electrophoretic mobility shift assays (EMSA), and transactivation assays using a consensus forkhead-domain binding site and a FOXO1 promoter fragment driving luciferase reporters.
Two novel and two previously reported recessive putative FOXE3 mutations were identified in patients diagnosed with primary aphakia. All parents studied were heterozygous for recessive mutations. In EMSAs three recessive mutants showed loss of function, and the two dominant mutants showed an altered mobility pattern when compared with wild-type protein. In transactivation assays all dominant and recessive mutants showed impaired function compared to wild-type. Highest levels of activity were observed in mutants that retained DNA-binding. Modelling the heterozygous state by mixing dominant mutant and wild-type FOXE3 resulted in reduced activity when compared with wild-type alone.
FOXE3 protein function was impaired by all dominant and recessive mutations investigated. A dominant-negative mechanism may account for the pathogenicity of dominant mutations, whereas FOXE3 activity above a level of dosage sensitivity is proposed to account for the normal phenotype in parents of children with recessive primary aphakia.
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