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 Kloss & 15 others 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*

*Corresponding author for this work

Research output: Contribution to journalArticle

38 Citations (Scopus)

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

Fingerprint

Angiopoietins
Glaucoma
Mutation
Anterior Chamber
Intraocular Pressure
Trabecular Meshwork
Haploinsufficiency
Proteins
Gene Dosage
Eye Diseases
Aqueous Humor
Blindness
Transgenic Mice
Blood Vessels
Ligands
Phenotype
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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), 2575-2587. https://doi.org/10.1172/JCI85830
Souma, Tomokazu ; Tompson, Stuart W. ; Thomson, Benjamin R. ; Siggs, Owen M. ; Kizhatil, Krishnakumar ; Yamaguchi, Shinji ; Feng, Liang ; Limviphuvadh, Vachiranee ; Whisenhunt, Kristina N. ; Maurer-Stroh, Sebastian ; Yanovitch, Tammy L. ; Kalaydjieva, Luba ; Azmanov, Dimitar N. ; Finzi, Simone ; Mauri, Lucia ; Javadiyan, Shahrbanou ; Souzeau, Emmanuelle ; Zhou, Tiger ; Hewitt, Alex W. ; Kloss, Bethany ; Burdon, Kathryn P. ; Mackey, David A. ; Allen, Keri F. ; Ruddle, Jonathan B. ; Lim, Sing Hui ; Rozen, Steve ; Tran-Viet, Khanh Nhat ; Liu, Xiaorong ; John, Simon ; Wiggs, Janey L. ; Pasutto, Francesca ; Craig, Jamie E. ; Jin, Jing ; Quaggin, Susan E ; Young, Terri L. / Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 7. pp. 2575-2587.
@article{85543903678f43cb8d905b9924d1a888,
title = "Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity",
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.",
author = "Tomokazu Souma and Tompson, {Stuart W.} and Thomson, {Benjamin R.} and Siggs, {Owen M.} and Krishnakumar Kizhatil and Shinji Yamaguchi and Liang Feng and Vachiranee Limviphuvadh and Whisenhunt, {Kristina N.} and Sebastian Maurer-Stroh and Yanovitch, {Tammy L.} and Luba Kalaydjieva and Azmanov, {Dimitar N.} and Simone Finzi and Lucia Mauri and Shahrbanou Javadiyan and Emmanuelle Souzeau and Tiger Zhou and Hewitt, {Alex W.} and Bethany Kloss and Burdon, {Kathryn P.} and Mackey, {David A.} and Allen, {Keri F.} and Ruddle, {Jonathan B.} and Lim, {Sing Hui} and Steve Rozen and Tran-Viet, {Khanh Nhat} and Xiaorong Liu and Simon John and Wiggs, {Janey L.} and Francesca Pasutto and Craig, {Jamie E.} and Jing Jin and Quaggin, {Susan E} and Young, {Terri L.}",
year = "2016",
month = "7",
day = "1",
doi = "10.1172/JCI85830",
language = "English (US)",
volume = "126",
pages = "2575--2587",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "7",

}

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, 'Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity', Journal of Clinical Investigation, vol. 126, no. 7, pp. 2575-2587. https://doi.org/10.1172/JCI85830

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

In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2575-2587.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

AU - Souma, Tomokazu

AU - Tompson, Stuart W.

AU - Thomson, Benjamin R.

AU - Siggs, Owen M.

AU - Kizhatil, Krishnakumar

AU - Yamaguchi, Shinji

AU - Feng, Liang

AU - Limviphuvadh, Vachiranee

AU - Whisenhunt, Kristina N.

AU - Maurer-Stroh, Sebastian

AU - Yanovitch, Tammy L.

AU - Kalaydjieva, Luba

AU - Azmanov, Dimitar N.

AU - Finzi, Simone

AU - Mauri, Lucia

AU - Javadiyan, Shahrbanou

AU - Souzeau, Emmanuelle

AU - Zhou, Tiger

AU - Hewitt, Alex W.

AU - Kloss, Bethany

AU - Burdon, Kathryn P.

AU - Mackey, David A.

AU - Allen, Keri F.

AU - Ruddle, Jonathan B.

AU - Lim, Sing Hui

AU - Rozen, Steve

AU - Tran-Viet, Khanh Nhat

AU - Liu, Xiaorong

AU - John, Simon

AU - Wiggs, Janey L.

AU - Pasutto, Francesca

AU - Craig, Jamie E.

AU - Jin, Jing

AU - Quaggin, Susan E

AU - Young, Terri L.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84978431523&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978431523&partnerID=8YFLogxK

U2 - 10.1172/JCI85830

DO - 10.1172/JCI85830

M3 - Article

VL - 126

SP - 2575

EP - 2587

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 7

ER -