title: Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies.
abstract: FOXE3 is a lens-specific transcription factor with a highly conserved forkhead domain previously implicated in congenital primary aphakia and anterior segment dysgenesis. Here, we identify new recessive FOXE3 mutations causative for microphthalmia, sclerocornea, primary aphakia, and glaucoma in two extended consanguineous families by SNP array genotyping followed by a candidate gene approach. Following an additional screen of 236 subjects with developmental eye anomalies, we report two further novel heterozygous mutations segregating in a dominant fashion in two different families. Although the dominant mutations were penetrant, they gave rise to highly variable phenotypes including iris and chorioretinal colobomas, Peters' anomaly, and isolated cataract (cerulean type and early onset adult nuclear and cortical cataract). Using in situ hybridization in human embryos, we demonstrate expression of FOXE3 restricted to lens tissue, predominantly in the anterior epithelium, suggesting that the extralenticular phenotypes caused by FOXE3 mutations are most likely to be secondary to abnormal lens formation. Our findings suggest that mutations in FOXE3 can give rise to a broad spectrum of eye anomalies, largely, but not exclusively related to lens development, and that both dominant and recessive inheritance patterns can be represented. We suggest including FOXE3 in the diagnostic genetic screening for these anomalies.
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Sibel Ugur
authors.initials: SU
authors.lastname: Iseri
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Osborne
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Alexander William
authors.initials: AW
authors.lastname: Wyatt
authors.forename: Ghazala
authors.initials: G
authors.lastname: Mirza
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Christian
authors.initials: C
authors.lastname: Kluck
authors.forename: Helen
authors.initials: H
authors.lastname: Herbert
authors.forename: Angela
authors.initials: A
authors.lastname: Martin
authors.forename: Muhammad Sajid
authors.initials: MS
authors.lastname: Hussain
authors.forename: J Richard O
authors.initials: JR
authors.lastname: Collin
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Ragge
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics*; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D017931:DNA Primers; C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors