Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

Souma T, Tompson SW, Thomson BR, Siggs OM, Kizhatil K, Yamaguchi S, Feng L, Limviphuvadh V, Whisenhunt KN, Maurer-Stroh S, Yanovitch TL, Kalaydjieva L, Azmanov DN, Finzi S, Mauri L, Javadiyan S, Souzeau E, Zhou T, Hewitt AW, Kloss B, Burdon KP, Mackey DA, Allen KF, Ruddle JB, Lim SH, Rozen S, Tran-Viet KN, Liu X, John S, Wiggs JL, Pasutto F, Craig JE, Jin J, Quaggin SE, Young TL (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 126

Pages Range: 2575-87

Journal Issue: 7

DOI: 10.1172/JCI85830

Abstract

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.

Involved external institutions

Northwestern University US United States (USA) (US) University of Wisconsin - Madison US United States (USA) (US) Ospedale Niguarda Ca' Granda / ASST Grande Ospedale Metropolitano Niguarda IT Italy (IT) University of Western Australia (UWA) AU Australia (AU) University of São Paulo / Universidade de São Paulo (USP) BR Brazil (BR) Flinders University AU Australia (AU) The University of Melbourne AU Australia (AU) Harvard University US United States (USA) (US) National University of Singapore (NUS) SG Singapore (SG) California State University Sacramento (CSUS) US United States (USA) (US) Howard Hughes Medical Institute US United States (USA) (US) Agency for Science, Technology and Research (A*STAR) SG Singapore (SG) University of Oklahoma US United States (USA) (US)

How to cite

APA:

Souma, T., Tompson, S.W., Thomson, B.R., Siggs, O.M., Kizhatil, K., Yamaguchi, S.,... Young, T.L. (2016). Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. Journal of Clinical Investigation, 126(7), 2575-87. https://dx.doi.org/10.1172/JCI85830

MLA:

Souma, Tomokazu, et al. "Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity." Journal of Clinical Investigation 126.7 (2016): 2575-87.

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