eCite Digital Repository

Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

Citation

Souma, T and Tompson, SW and Thomson, BR and Siggs, OM and Kizhatil, K and Yamaguchi, S and Feng, L and Limviphuvadh, V and Whisenhunt, KN and Maurer-Stroh, S and Yanovitch, TL and Kalaydjieva, L and Azmanov, DN and Finzi, S and Mauri, L and Javadiyan, S and Souzeau, E and Zhou, T and Hewitt, AW and Kloss, B and Burdon, KP and Mackey, DA and Allen, KF and Ruddle, JB and Lim, S-H and Rozen, S and Tran-Viet, K-N and Liu, X and John, S and Wiggs, JL and Pasutto, F and Craig, JE and Jin, J and Quaggin, SE and Young, TL, Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity, Journal of Clinical Investigation, 126, (7) pp. 2575-2587. ISSN 0021-9738 (2016) [Refereed Article]


Preview
PDF
2Mb
  

Copyright Statement

Copyright 2016 American Society of Clinical Investigation

DOI: doi:10.1172/JCI85830

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Ophthalmology and Optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Hearing, Vision, Speech and Their Disorders
Author:Hewitt, AW (Professor Alex Hewitt)
Author:Burdon, KP (Associate Professor Kathryn Burdon)
Author:Mackey, DA (Professor David Mackey)
ID Code:110500
Year Published:2016
Web of Science® Times Cited:26
Deposited By:Menzies Institute for Medical Research
Deposited On:2016-07-28
Last Modified:2017-11-06
Downloads:36 View Download Statistics

Repository Staff Only: item control page