Abstract
Purpose: :
Development of the anterior segment of the eye is a complex process that depends on multiple inductive events and coordinated interactions between cells of ectodermal, neuroectodermal, and neural crest origin. Disturbances in this process can cause glaucoma, cataract, leucoma, or other conditions that lead to vision impairment or blindness. Foxe3 encodes a forkhead transcription factor that is expressed in the lens anlage during eye formation and in lens epithelium thereafter. Foxe3 is essential for proliferation, prevention of premature differentiation, and protection against apoptosis in the lens epithelium. Mutations in FOXe3 have been previously described in cases of congenital primary aphakia and Peter’s anomaly. More recently, homozygous and heterozygous FOXe3 mutation have been associated to a spectrum of anterior segment anomalies including iris and chorioretinal colobomas, Peter`s anomaly, isolated cataract, and sclerocornea. The aim of this work is to present the clinical and genetic description of two Mexican families segregating an autosomal recessive complex of sclerocornea-primary congenital aphakia which results from a novel missense mutation in FOXe3.
Methods: :
A total of five affected patients pertaining to 2 families from the Central region of Mexico were ascertained. Unaffected relatives were also included. Ophthalmologic examination included slit lamp biomicroscopy and A- and B- mode ultrasonography. Genetic analysis comprised PCR amplification of the FOXe3 coding region and automated nucleotidic sequence of PCR amplicons.
Results: :
All affected subjects from both families exhibited a homogeneous phenotype characterized by bilateral sclerocornea totalis. In addition, USG study revealed congenital aphakia. Some subjects also exhibited optic disc coloboma. Mutational analysis of FOXe3 revealed a c.292T>C substitution which predicts a novel Tyr98His mutation. Sequence alignment among several FOXE3 proteins revealed that Tyrosine 98 is highly conserved among species. The mutation was observed in heterozygous state in obligate carriers and was absent from a panel of 210 control alleles tested by direct sequencing or PCR-RFLP (FokI).
Conclusions: :
Two novel families with the sclerocornea-aphakia complex due to FOXe3 mutations are presented. A novel mutation affecting a highly conserved tyrosine was demonstrated. The relative close geographical origin of these two families suggests a founder effect mutation. Our results add to the clinical and mutational spectrum of the growing group of anterior segment developmental anomalies linked to FOXe3.
Keywords: genetics • cornea: basic science