Foxe3 haploinsufficiency in mice: a model for Peters' anomaly.
OBJECTIVE
To evaluate the importance in anterior segment dysgenesis of genetic variation in Foxe3, a gene encoding a forkhead transcription factor specifically expressed in the lens.


METHODS
The phenotype of mice heterozygous for a mutation in the DNA-binding domain of Foxe3 was examined from histologic sections, and DNA binding by the encoded protein was investigated by gel-shift assay. FOXE3 from human patients with Peters' anomaly was PCR amplified and sequenced.


RESULTS
The dysgenetic lens (dyl) allele of Foxe3 was found to encode a protein unable to bind DNA. Approximately 40% of mice heterozygous for Foxe3(dyl) have corneal and lenticular defects. The phenotype is variable but typically consists of the equivalent of Peters' anomaly in humans, with central corneal opacity, keratolenticular adhesion, and, in some cases, anterior polar cataract. In a small cohort (n = 13) of patients with Peters' anomaly, shown to be normal in the PAX6 locus, one individual was found to be heterozygous for a nonconservative missense mutation in FOXE3. The mutation, which does not occur in 116 chromosomes from a control population, substitutes leucine for arginine 90 at a highly conserved position in the forkhead domain.


CONCLUSIONS
Haploinsufficiency of Foxe3 in a mouse model causes anterior segment dysgenesis similar to Peters' anomaly. Although causality could not be shown in the human case, the presence of a rare, nonconservative substitution in FOXE3 of a patient with Peters' anomaly is interesting, in light of the phenotypic similarities with the mutant mice.
Ormestad
Mattias
M
Department of Molecular Biology, The Lundberg Laboratory, Gothenburg University, Medicinaregatan 9C, SE-405 30 Gothenburg, Sweden.
Blixt
Asa
A
Churchill
Amanda
A
Martinsson
Tommy
T
Enerbäck
Sven
S
Carlsson
Peter
P
D000595:Amino Acid Sequence; D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003318:Corneal Opacity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors; D006239:Haplotypes; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D021101:Radiation Hybrid Mapping; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors; C498612:Foxe3 protein, mouse; D014157:Transcription Factors