Novel Anterior Segment Phenotypes Resulting from Forkhead Gene Alterations: Evidence for Cross-Species Conservation of Function

Abstract

Normal corneal development is dependent on the precise dose and levels of activity of certain forkhead transcription factors. The altered corneal thickness attributable to increased forkhead gene dosage is particularly important, because it may affect the clinical management of certain glaucoma subtypes and lead to excessive treatment. The FOXC1 and Foxe3 data, taken together with the novel ocular phenotypes of FOXC2 mutations, highlight the remarkable cross-species conservation of function among forkhead genes.

A lymphatic defect causes ocular hypertension and glaucoma in mice

“…In older animals, our data suggest Corneal neovascularization and glaucoma have been described in patients with Axenfeld-Rieger syndrome due to mutations in FOXC1, and Foxc1 haploinsufficient mice exhibit defects in the anterior chamber and Schlemm's canal, suggesting a link to this molecular pathway (10). In mice, a similar phenotype has been described for the related transcription factor FOXC2 (10,12). Intriguingly, the downstream targets of FOXC1/2 responsible for these phenotypes have not been elucidated.…”

Heritability of Central Corneal Thickness in Chinese: The Guangzhou Twin Eye Study

“…Some rare disorders have been found to have a distinct CCT value in clinical studies. It is noteworthy that some of them are glaucoma-associated developmental syndromes, such as iris hypoplasia, 29 aniridia, 30 dysgenetic lens, 29 pseudoexfoliation syndrome, 31 Peters anomaly, 32 and Axenfeld-Rieger Syndrome. 33 The use of objective measurement for phenotyping is an important issue in conducting twin studies.…”

Zebrafish pitx3 is necessary for normal lens and retinal development

“…While both the ak and pitx3 morphant lenses exhibit defective lens differentiation, the ak defect is manifested earlier in development and results in the complete failure of lens formation. These differences may reflect the relative strength of the phenotypes (Gage et al, 1999b;Lehmann et al, 2003;Ormestad et al, 2002), as the ak mutant represents the null condition and the pitx3 morphant may retain some functional Pitx3 protein. This residual Pitx3 activity may be sufficient for the morphant lens to develop further than the ak lens.…”