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Human Molecular Genetics, 2000, Vol. 9, No. 7 1021-1032
© 2000 Oxford University Press

Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development

Richard S. Smith1,2, Adriana Zabaleta2, Tsutomu Kume1,3, Olga V. Savinova2, Susan H. Kidson4, Janice E. Martin1,2, Darryl Y. Nishimura5, Wallace L. M. Alward6, Brigid L. M. Hogan1,3 and Simon W. M. John1,2,7,+

1The Howard Hughes Medical Institute and 2The Jackson Laboratory, Bar Harbor, ME, USA, 3Department of Cell Biology, Vanderbilt University Medical Center, Nashville, TN, USA, 4Department of Anatomy and Cell Biology, University of Cape Town, Observatory 7925, Cape Town, South Africa, Departments of 5Pediatrics and 6Ophthalmology, University of Iowa, Iowa City, IA, USA and 7Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA

Anterior segment developmental disorders, including Axenfeld–Rieger anomaly (ARA), variably associate with harmfully elevated intraocular pressure (IOP), which causes glaucoma. Clinically observed dysgenesis does not correlate with IOP, however, and the etiology of glaucoma development is not understood. The forkhead transcription factor genes Foxc1 (formerly Mf1) and Foxc2 (formerly Mfh1) are expressed in the mesenchyme from which the ocular drainage structures derive. Mutations in the human homolog of Foxc1, FKHL7, cause dominant anterior segment defects and glaucoma in various families. We show that Foxc1+/– mice have anterior segment abnormalities similar to those reported in human patients. These abnormalities include small or absent Schlemm’s canal, aberrantly developed trabecular meshwork, iris hypoplasia, 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 matrix synthesis or organization may contribute to development of the ocular phenotypes. Despite the abnormalities in ocular drainage structures in Foxc1+/– mice, IOP was normal in almost all mice analyzed, on all genetic backgrounds 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 FKHL14) to produce a phenotype with elevated IOP and glaucoma.

+ To whom correspondence should be addressed at: The Howard Hughes Medical Institute, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. Tel: +1 207 288 6496; Fax: +1 207 288 6079; Email: swmj@jax.org


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