Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.

Abstract

Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.

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Citation

Published Version (Please cite this version)

10.1172/jci85830

Publication Info

Souma, Tomokazu, Stuart W Tompson, Benjamin R Thomson, Owen M Siggs, Krishnakumar Kizhatil, Shinji Yamaguchi, Liang Feng, Vachiranee Limviphuvadh, et al. (2016). Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. The Journal of clinical investigation, 126(7). 10.1172/jci85830 Retrieved from https://hdl.handle.net/10161/16648.

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Scholars@Duke

Souma

Tomokazu Souma

Assistant Professor in Medicine
Rozen

Steven George Rozen

Professor in Biostatistics & Bioinformatics
Young

Terri Lois Young

Adjunct Professor in Ophthalmology

Terri L. Young, M.D., M.B.A. is a board-certified clinician-scientist ophthalmologist.  She is a Professor of Ophthalmology, Pediatrics, and Medicine at Duke University School of Medicine.  She is a Professor of Neuroscience at the Duke- National University of Singapore Graduate Medical School, with adjunct appointments at the Singapore Eye Research Institute and the Saw Swee Hock School of Public Health, National University of Singapore.  She is the founding Director of the Duke Eye Center Ophthalmic Genetics Program.  She is also the Associate Director of the Duke School of Medicine Clinical and Translational Sciences Award Predoctoral Research TL1 Training Award.

Dr. Young's clinical interests include ophthalmic genetics, pediatric eye disease including pediatric cataracts and retinal disorder, and the surgical correction of strabismus/ eye misalignment in children and adults.  Her laboratory research focuses on the genetic studies of refractive errors, eye development and growth, primary congenital glaucoma, retinal and corneal dystrophies, and other heritable disorders.  Her research program includes the development of animal models in zebrafish and mice for ocular diseases based on our understanding of genetic influences in humans.   

Dr. Young is an editorial board member of Experimental Eye Research, World Journal of Ophthalmology, Journal of Ophthalmology, and past editorial board member of the Journal of the Association of Pediatric Ophthalmology and Strabismus.   She has published over 180 scientific refereed articles, and multiple book chapters, reviews and abstracts.  Dr. Young has served as a strategic consultant to the National Eye Institute (NEI) and the National Human Genome Research Institute.  She has served as a National Institutes of Health (NIH) study section member for 14 years, and is currently a permanent member of the Diseases and Pathophysiology of the Visual System study section.  She also presently serves as a board member of the NIH NEI Scientific Board of Counselors.  She is the American Association of Ophthalmology Pediatric Ophthalmology Program Committee Chair, and the Association for Research in Vision and Ophthalmology Program Committee Vice Chair of the Biochemistry and Molecular Biology Section.  She is the Treasurer of Women in Ophthalmology, Inc. 

Dr. Young has garnered several prestigious awards as a Fellow of the Philadelphia College of Physicians, the American Ophthalmological Society, and the Association of Research in Vision and Ophthalmology.  She has garnered an Honor Award from the American Association of Pediatric Ophthalmology and Strabismus, and a Senior Honor Award from the American Association of Ophthalmology.  She is an international speaker, with multiple named lectureships.  She has been honored with citations of "Best Doctors in North Carolina", "America's Top Ophthalmologists", and in Becker's Review of "135 Leading Ophthalmolgists in America" for several years.  She has also been featured in the NIH National Library of Medicine "Changing the Face of Medicine" exhibit. (2004)


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