Abstract
Anterior segment dysgenesis (ASD) is characterised by an abnormal migration of neural crest cells or an aberrant differentiation of the mesenchymal cells during the formation of the eye's anterior segment. These abnormalities result in multiple tissue defects affecting the iris, cornea and drainage structures of the iridocorneal angle including the ciliary body, trabecular meshwork and Schlemm's canal. In some cases, abnormal ASD development leads to glaucoma, which is usually associated with increased intraocular pressure. Haploinsufficiency through mutation or chromosomal deletion of the human FOXC1 transcription factor gene or duplications of the 6p25 region is associated with a spectrum of ocular abnormalities including ASD. However, mapping data and phenotype analysis of human deletions suggests that an additional locus for this condition may be present in the same chromosomal region as FOXC1. DHPLC screening of ENU mutagenised mouse archival tissue revealed five novel mouse Foxf2 mutations. Re-derivation of one of these (the Foxf2 W174R mouse lineage) resulted in heterozygote mice that exhibited thinning of the iris stroma, hyperplasia of the trabecular meshwork, small or absent Schlemm's canal and a reduction in the iridocorneal angle. Homozygous E18.5 mice showed absence of ciliary body projections, demonstrating a critical role for Foxf2 in the developing eye. These data provide evidence that the Foxf2 gene, separated from Foxc1 by less than 70 kb of genomic sequence (250 kb in human DNA), may explain human abnormalities in some cases of ASD where FOXC1 has been excluded genetically.
Highlights
Anterior segment dysgenesis covers a spectrum of disorders affecting the iris, cornea, trabecular meshwork and Schlemm’s canal of the eye, which can result in abnormal aqueous humor drainage from the eye leading to raised intraocular pressure and glaucoma [1]
We describe the genetic analysis of an identified Foxf2 mutation and the phenotypic features of the affected animals. These analyses suggest Foxf2 is essential for normal anterior segment development, and that the FOXF2 gene should be considered as an additional candidate for anterior segment dysgenesis in humans
Chromosome 6p25 is a major locus for anterior segment dysgenesis (ASD)
Summary
Anterior segment dysgenesis covers a spectrum of disorders affecting the iris, cornea, trabecular meshwork and Schlemm’s canal of the eye, which can result in abnormal aqueous humor drainage from the eye leading to raised intraocular pressure and glaucoma [1]. These abnormalities result from a primary defect in the migration and differentiation of neural crest cells that contribute to the development of the anterior segment structures [2]. Inactivation of this growth factor in mouse neural crest cells results in malformed trabecular meshwork, ciliary body and corneal endothelium cells [15]
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