Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

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 invol...

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Bibliographic Details
Published in:The Journal of clinical investigation 2016-07, Vol.126 (7), p.2575-2587
Main Authors: Souma, Tomokazu, Tompson, Stuart W, Thomson, Benjamin R, Siggs, Owen M, Kizhatil, Krishnakumar, Yamaguchi, Shinji, Feng, Liang, Limviphuvadh, Vachiranee, Whisenhunt, Kristina N, Maurer-Stroh, Sebastian, Yanovitch, Tammy L, Kalaydjieva, Luba, Azmanov, Dimitar N, Finzi, Simone, Mauri, Lucia, Javadiyan, Shahrbanou, Souzeau, Emmanuelle, Zhou, Tiger, Hewitt, Alex W, Kloss, Bethany, Burdon, Kathryn P, Mackey, David A, Allen, Keri F, Ruddle, Jonathan B, Lim, Sing-Hui, Rozen, Steve, Tran-Viet, Khanh-Nhat, Liu, Xiaorong, John, Simon, Wiggs, Janey L, Pasutto, Francesca, Craig, Jamie E, Jin, Jing, Quaggin, Susan E, Young, Terri L
Format: Article
Language:English
Subjects:
Angiopoietins - metabolism
Animals
Care and treatment
Exome
Family Health
Gene Dosage
Gene Expression Regulation
Gene mutations
Genetic aspects
Glaucoma
Glaucoma - congenital
Glaucoma - genetics
Health aspects
Humans
Identification and classification
Intraocular Pressure
Ligands
Mice
Mice, Knockout
Mice, Transgenic
Mutation
Mutation, Missense
Pedigree
Phenotype
Phosphorylation
Receptor, TIE-2 - genetics
Signal Transduction
Trabecular Meshwork
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI85830