The anterior segment abnormalities observed in
Foxe3 dyl/+ heterozygous mice closely resemble Peters’ anomaly.
34 35 Most cases of this congenital defect of the anterior chamber of the eye, with central adhesion between lens and cornea and central leucoma as frequent manifestations, are sporadic, and in only a few cases have mutations been reported.
PAX6 mutations are usually associated with aniridia, but are occasionally found in Peters’ anomaly.
12 Doward et al.
27 described a
PITX2 mutation in a child with Rieger syndrome, who exhibited some ocular features in one eye that overlap the spectrum of Peters’ anomaly. Mutations in
CYP1B1 is a major cause of primary congenital glaucoma,
36 and mutations in this gene have been diagnosed in one case of Peters’ anomaly.
28 However, neither of these genes is mutated in most patients with Peters’ anomaly, and no other genes have yet been found to be involved.
29 We sequenced the
FOXE3 gene from 13 individuals with diagnosis of Peters’ anomaly. Occurrence in nine was sporadic and may represent recessive inheritance or new dominant mutations and in four was familial (from four families). Of these four families, three showed dominant inheritance, and one (with consanguineous parents) exhibited a recessive pattern. The clinical details for these individuals have been described previously, and they were shown to be negative for mutations in the coding region of the
PAX6 gene.
29 All patients in this study were born with bilateral congenital corneal opacities with or without cataracts. Apart from translationally silent polymorphisms, we found a
FOXE3 mutation in a familial case of Peters’ anomaly (patient LAS) with eccentric corneal opacities and glaucoma but not cataract.
29 The sequence trace showed a mixed T/G peak, indicative of heterozygosity
(Fig. 5c) . To verify the presence of two alleles, we cloned the PCR fragments and sequenced individual plasmid clones, which had either a T or a G in the affected position
(Figs. 5b 5d) . The G→T mutation occurs in cDNA position 524 and causes an Arg90Leu substitution, located in the DNA-binding domain of FOXE3 (
Figs. 1b ;
5b 5c 5d ). The mutant protein binds DNA when produced by in vitro translation and tested in a gel-shift assay (data not shown), although we have not performed a quantitative measurement of the affinity. It gives rise to a complex with slightly higher mobility than the normal protein, which may be caused by the decreased net charge from the Arg→Leu substitution, or an altered three-dimensional (3-D) structure. To exclude the possibility that the mutation represents a polymorphism in
FOXE3, we sequenced the relevant region in 58 healthy control subjects with similar ethnic background (34 English and 24 Swedish). None of these had the G524T mutation. Semina et al.
26 screened the
FOXE3 gene from 251 individuals—patients with ocular disorders and normal control subjects—for mutations and listed all polymorphisms detected. They found five single-nucleotide polymorphisms with rare allele frequencies of between 1% and 32%, all of which are translationally silent or cause conservative substitutions. The G524T mutation was not detected in this sample of more than 500 chromosomes. Therefore, based on our own and published data, we exclude the possibility that Arg90Leu represents a common polymorphism.