Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

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 KlossKathryn 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

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 Te k 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 Te k 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.

Original languageEnglish (US)
Pages (from-to)2575-2587
Number of pages13
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • Medicine(all)

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