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

Authors
  • Thomson, Benjamin R1, 2
  • Souma, Tomokazu1, 2
  • Tompson, Stuart W3
  • Onay, Tuncer1, 2
  • Kizhatil, Krishnakumar4
  • Siggs, Owen M5
  • Feng, Liang6
  • Whisenhunt, Kristina N3
  • Yanovitch, Tammy L7
  • Kalaydjieva, Luba8
  • Azmanov, Dimitar N8, 9
  • Finzi, Simone10
  • Tanna, Christine E1, 2
  • Hewitt, Alex W11, 12, 13
  • Mackey, David A12, 13
  • Bradfield, Yasmin S3
  • Souzeau, Emmanuelle5
  • Javadiyan, Shari5
  • Wiggs, Janey L14
  • Pasutto, Francesca15
  • And 6 more
  • 1 Feinberg Cardiovascular Research Institute and.
  • 2 Division of Nephrology/Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 3 Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 4 Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, Maine, USA.
  • 5 Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia. , (Australia)
  • 6 Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 7 Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma, Oklahoma City, Oklahoma, USA.
  • 8 Harry Perkins Institute of Medical Research and Centre for Medical Research, University of Western Australia, Perth, Western Australia, Australia. , (Australia)
  • 9 Department of Diagnostic Genomics, PathWest, QEII Medical Centre, Perth, Western Australia, Australia. , (Australia)
  • 10 Department of Ophthalmology, Hospital das Clínicas of University of São Paulo, São Paulo, Brazil. , (Brazil)
  • 11 Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia. , (Australia)
  • 12 Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia. , (Australia)
  • 13 Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. , (Australia)
  • 14 Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
  • 15 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. , (Germany)
Type
Published Article
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Publication Date
Nov 06, 2017
Identifiers
DOI: 10.1172/JCI95545
PMID: 29106382
Source
Medline
Keywords
License
Unknown

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.

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