Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 12, Pages 4421-4436Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI95545
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Funding
- NIH [R01 HL124120, R01 EY025799, R01 EY014685]
- Research to Prevent Blindness Inc.
- University of Wisconsin
- March of Dimes Foundation
- NEI [P30EY014104]
- Howard Hughes Medical Center
- Ophthalmic Research Institute of Australia
- Channel Seven Children's Research Foundation
- Department of Innovation, Industry, Science and Research (Australia)
- National Health and Medical Research Council of Australia
- Japan Society for the Promotion of Science
- Mallinckrodt Pharmaceuticals
- NCI CCSG [P30 CA060553]
- Northwestern University Transgenic and Targeted Mutagenesis Laboratory
- Cancer Center Support Grant [NCI CA060553]
- Vision Core Grant [NEI P30EY016665]
- University of Wisconsin-Madison Department of Ophthalmology and Visual Sciences
- EY [11721]
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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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