Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity

T. Souma, S.W. Tompson, B.R. Thomson, O.M. Siggs, K. Kizhatil, S. Yamaguchi, L. Feng, V. Limviphuvadh, K.N. Whisenhunt, S. Maurer-Stroh, T.L. Yanovitch, Luba Kalaydjieva, Dimitar Azmanov, S. Finzi, L. Mauri, S. Javadiyan, E. Souzeau, T. Zhou, Alex Hewitt, B. Kloss & 15 others K.P. Burdon, David Mackey, K.F. Allen, J.B. Ruddle, S.H. Lim, S. Rozen, K.N. Tran-Viet, X. Liu, S. John, J.L. Wiggs, F. Pasutto, J.E. Craig, J. Jin, S.E. Quaggin, T.L. Young

Research output: Contribution to journalArticle

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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
Pages (from-to)2575-2587
JournalJournal of Clinical Investigation
Volume126
Issue number7
Early online date6 Jun 2016
DOIs
Publication statusPublished - Jul 2016

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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

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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, T. ; Tompson, S.W. ; Thomson, B.R. ; Siggs, O.M. ; Kizhatil, K. ; Yamaguchi, S. ; Feng, L. ; Limviphuvadh, V. ; Whisenhunt, K.N. ; Maurer-Stroh, S. ; Yanovitch, T.L. ; Kalaydjieva, Luba ; Azmanov, Dimitar ; Finzi, S. ; Mauri, L. ; Javadiyan, S. ; Souzeau, E. ; Zhou, T. ; Hewitt, Alex ; Kloss, B. ; Burdon, K.P. ; Mackey, David ; Allen, K.F. ; Ruddle, J.B. ; Lim, S.H. ; Rozen, S. ; Tran-Viet, K.N. ; Liu, X. ; John, S. ; Wiggs, J.L. ; Pasutto, F. ; Craig, J.E. ; Jin, J. ; Quaggin, S.E. ; Young, T.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.
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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 = "T. Souma and S.W. Tompson and B.R. Thomson and O.M. Siggs and K. Kizhatil and S. Yamaguchi and L. Feng and V. Limviphuvadh and K.N. Whisenhunt and S. Maurer-Stroh and T.L. Yanovitch and Luba Kalaydjieva and Dimitar Azmanov and S. Finzi and L. Mauri and S. Javadiyan and E. Souzeau and T. Zhou and Alex Hewitt and B. Kloss and K.P. Burdon and David Mackey and K.F. Allen and J.B. Ruddle and S.H. Lim and S. Rozen and K.N. Tran-Viet and X. Liu and S. John and J.L. Wiggs and F. Pasutto and J.E. Craig and J. Jin and S.E. Quaggin and T.L. Young",
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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, D, Finzi, S, Mauri, L, Javadiyan, S, Souzeau, E, Zhou, T, Hewitt, A, Kloss, B, Burdon, KP, Mackey, D, 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, T.; Tompson, S.W.; Thomson, B.R.; Siggs, O.M.; Kizhatil, K.; Yamaguchi, S.; Feng, L.; Limviphuvadh, V.; Whisenhunt, K.N.; Maurer-Stroh, S.; Yanovitch, T.L.; Kalaydjieva, Luba; Azmanov, Dimitar; Finzi, S.; Mauri, L.; Javadiyan, S.; Souzeau, E.; Zhou, T.; Hewitt, Alex; Kloss, B.; Burdon, K.P.; Mackey, David; Allen, K.F.; Ruddle, J.B.; Lim, S.H.; Rozen, S.; Tran-Viet, K.N.; Liu, X.; John, S.; Wiggs, J.L.; Pasutto, F.; Craig, J.E.; Jin, J.; Quaggin, S.E.; Young, T.L.

In: Journal of Clinical Investigation, Vol. 126, No. 7, 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, T.

AU - Tompson, S.W.

AU - Thomson, B.R.

AU - Siggs, O.M.

AU - Kizhatil, K.

AU - Yamaguchi, S.

AU - Feng, L.

AU - Limviphuvadh, V.

AU - Whisenhunt, K.N.

AU - Maurer-Stroh, S.

AU - Yanovitch, T.L.

AU - Kalaydjieva, Luba

AU - Azmanov, Dimitar

AU - Finzi, S.

AU - Mauri, L.

AU - Javadiyan, S.

AU - Souzeau, E.

AU - Zhou, T.

AU - Hewitt, Alex

AU - Kloss, B.

AU - Burdon, K.P.

AU - Mackey, David

AU - Allen, K.F.

AU - Ruddle, J.B.

AU - Lim, S.H.

AU - Rozen, S.

AU - Tran-Viet, K.N.

AU - Liu, X.

AU - John, S.

AU - Wiggs, J.L.

AU - Pasutto, F.

AU - Craig, J.E.

AU - Jin, J.

AU - Quaggin, S.E.

AU - Young, T.L.

PY - 2016/7

Y1 - 2016/7

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.

U2 - 10.1172/JCI85830

DO - 10.1172/JCI85830

M3 - Article

VL - 126

SP - 2575

EP - 2587

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

SN - 0021-9738

IS - 7

ER -