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Functional Analysis of FOXE 3 Mutations Causing Dominant and Recessive Ocular Anterior Segment Disease
Author(s) -
Islam Lily,
Kelberman Daniel,
Williamson Laura,
Lewis Nicola,
Glindzicz Maria Bitner,
Nischal Ken K.,
Sowden Jane C.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22741
Subject(s) - biology , mutant , genetics , haploinsufficiency , phenotype , mutation , loss function , wild type , function (biology) , gene
Mutations in FOXE 3 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 FOXE 3 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 FOXE 3 mutations identified in patients impair protein function with differential effects.