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Angiopoietin-1 is required for Schlemm's canal development in mice and humans

Citation

Thomson, BR and Souma, T and Tompson, SW and Onay, T and Kizhatil, K and Siggs, OM and Feng, L and Whisenhunt, KN and Yanovitch, TL and Kalaydjieva, L and Azmanov, DN and Finzi, S and Tanna, CE and Hewitt, AW and Mackey, DA and Bradfield, YS and Souzeau, E and Javadiyan, S and Wiggs, JL and Pasutto, F and Liu, X and John, SWM and Craig, JE and Jin, J and Young, TL and Quaggin, SE, Angiopoietin-1 is required for Schlemm's canal development in mice and humans, Journal of Clinical Investigation pp. 1-16. ISSN 0021-9738 (2017) [Refereed Article]


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DOI: doi:10.1172/JCI95545

Abstract

Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.

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 (Dr Alex Hewitt)
Author:Mackey, DA (Professor David Mackey)
ID Code:122455
Year Published:2017
Web of Science® Times Cited:20
Deposited By:Menzies Institute for Medical Research
Deposited On:2017-11-15
Last Modified:2017-11-15
Downloads:0

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