@article{349702739ea0469b942e1a9c6c5ba85b,
title = "Angiopoietin-1 is required for Schlemm{\textquoteright}s canal development in mice and humans",
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{\textquoteright}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.",
author = "Thomson, {Benjamin R.} and Tomokazu Souma and Tompson, {Stuart W.} and Tuncer Onay and Krishnakumar Kizhatil and Siggs, {Owen M.} and Liang Feng and Whisenhunt, {Kristina N.} and Yanovitch, {Tammy L.} and Luba Kalaydjieva and Azmanov, {Dimitar N.} and Simone Finzi and Tanna, {Christine E.} and Hewitt, {Alex W.} and Mackey, {David A.} and Bradfield, {Yasmin S.} and Emmanuelle Souzeau and Shari Javadiyan and Wiggs, {Janey L.} and Francesca Pasutto and Xiaorong Liu and John, {Simon W.M.} and Craig, {Jamie E.} and Jing Jin and Young, {Terri L.} and Quaggin, {Susan E.}",
note = "Funding Information: We thank the patient subjects for participating in this study. We also thank John Pater, Joanna Black, Jane Kelly, Sharon Freedman, Ivailo Tournev, and Sylvia Cherninkova for clinical input, Daniel Berner for sequencing assistance, and Veronica Ramirez, Ronnie Anderson, and Andrew Wei for technical assistance. Angpt1GFP mice were a gift from Sean Morrison, and Prox1tdTomato mice were a gift of Guillermo Oliver. This study was funded by NIH R01 HL124120 and R01 EY025799 (to SEQ); and NIH R01 EY014685, the Research to Prevent Blindness Inc. Lew R. Wasserman Award, and the University of Wisconsin Centennial Scholars Award (to TL Young). This work was also supported by grants from the March of Dimes Foundation and NEI P30EY014104 (to JLW), Howard Hughes Medical Center and EY 11721 (to SJ and KK), the Ophthalmic Research Institute of Australia, the Channel Seven Children{\textquoteright}s Research Foundation, the Department of Innovation, Industry, Science and Research (Australia), and the National Health and Medical Research Council of Australia. TS is supported by fellowship grants from the Japan Society for the Promotion of Science and Mallinckrodt Pharmaceuticals. Imaging was performed at the Northwestern University Center for Advanced Microscopy supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This work was supported by the Northwestern University Transgenic and Targeted Mutagenesis Laboratory and a Cancer Center Support Grant (NCI CA060553). We also acknowledge support from Vision Core Grant NEI P30EY016665 and an unrestricted Research to Prevent Blindness grant of the University of Wisconsin–Madison Department of Ophthalmology and Visual Sciences.",
year = "2017",
month = dec,
day = "1",
doi = "10.1172/JCI95545",
language = "English (US)",
volume = "127",
pages = "4421--4436",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",
}
