2. Academic Validation
  3. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

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.
Tomokazu Souma,  Stuart W Tompson,  Benjamin R Thomson,  Owen M Siggs,  Krishnakumar Kizhatil,  Shinji Yamaguchi,  Liang Feng,  Vachiranee Limviphuvadh,  Kristina N Whisenhunt,  Sebastian Maurer-Stroh,  Tammy L Yanovitch,  Luba Kalaydjieva,  Dimitar N Azmanov,  Simone Finzi,  Lucia Mauri,  Shahrbanou Javadiyan,  Emmanuelle Souzeau,  Tiger Zhou,  Alex W Hewitt,  Bethany Kloss,  Kathryn P Burdon,  David A Mackey,  Keri F Allen,  Jonathan B Ruddle,  Sing-Hui Lim,  Steve Rozen,  Khanh-Nhat Tran-Viet,  Xiaorong Liu,  Simon John,  Janey L Wiggs,  Francesca Pasutto,  Jamie E Craig,  Jing Jin,  Susan E Quaggin,  Terri L Young
PMID: 27270174 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.

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