Author(s): 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. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J Clin Invest. 2016 Jul 1;126(7):2575-87. doi: 10.1172/JCI85830. Epub 2016 Jun 6. PMID 27270174
Journal: The Journal Of Clinical Investigation, Volume 126, Issue 7, Jul 2016
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.