Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies.
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.
Iseri
Sibel Ugur
SU
Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, United Kingdom.
Osborne
Robert J
RJ
Farrall
Martin
M
Wyatt
Alexander William
AW
Mirza
Ghazala
G
Nürnberg
Gudrun
G
Kluck
Christian
C
Herbert
Helen
H
Martin
Angela
A
Hussain
Muhammad Sajid
MS
Collin
J Richard O
JR
Lathrop
Mark
M
Nürnberg
Peter
P
Ragoussis
Jiannis
J
Ragge
Nicola K
NK
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
D017931:DNA Primers; C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors