Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity
journal contributionposted on 2023-05-18, 21:14 authored by 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, Alexander HewittAlexander Hewitt, Kloss, B, Kathryn BurdonKathryn Burdon, David MackeyDavid Mackey, Allen, KF, Ruddle, JB, Lim, S-H, Rozen, S, Tran-Viet, K-N, Liu, X, John, S, Wiggs, JL, Pasutto, F, Craig, JE, Jin, J, Quaggin, SE, Young, TL
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.
Publication titleJournal of Clinical Investigation
Department/SchoolMenzies Institute for Medical Research
PublisherAmerican Society for Clinical Investigation
Place of publicationUnited States
Rights statementCopyright 2016 American Society of Clinical Investigation