Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results inaberrant ocular development

Anterior segment developmental disorders, including Axenfeld-Rieger anomaly (ARA), variably associate with harmfully elevated intraocular pressure (IO P), which causes glaucoma, Clinically observed dysgenesis does not correlat e with IOP, however, and the etiology of glaucoma development is not unders tood. The fork-head transcription factor genes Foxc1 (formerly Mf1) and Fox c2 (formerly Mfh1) are expressed in the mesenchyme from which the ocular dr ainage structures derive, Mutations in the human homolog of Foxc1, FKHL7, c ause dominant anterior segment defects and glaucoma in various families. We show that Foxc1(+/-) mice have anterior segment abnormalities similar to t hose reported in human patients, These abnormalities include small or absen t Schlemm's canal, aberrantly developed trabecular meshwork, iris hypoplasi a, severely eccentric pupils and displaced Schwalbe's line. The penetrance of clinically obvious abnormalities varies with genetic background. In some affected eyes, collagen bundles were half normal diameter, or collagen and elastic tissue were very sparse, Thus, abnormalities in extracellular matr ix synthesis or organization may contribute to development of the ocular ph enotypes. Despite the abnormalities in ocular drainage structures in Foxc1( +/-) mice, IOP was normal in almost all mice analyzed, on all genetic backg rounds and at all ages, Similar abnormalities were found in Foxc2(+/-) mice , but no disease-associated mutations were identified in the human homolog FKHL14 in 32 ARA patients, Foxc1(+/-) and Foxc2(+/-) mice are useful models for studying anterior segment development and its anomalies, and may allow identification of genes that interact with Foxc1 and Foxc2 (or FKHL7 and F KHL14) to produce a phenotype with elevated IOP and glaucoma.