Abstract
Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm’s canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4421-4436 |
| Number of pages | 16 |
| Journal | Journal of Clinical Investigation |
| Volume | 127 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2017 |
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ASJC Scopus subject areas
- Medicine(all)
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Angiopoietin-1 is required for Schlemm’s canal development in mice and humans. / Thomson, Benjamin R.; Souma, Tomokazu; Tompson, Stuart W.; Onay, Tuncer; Kizhatil, Krishnakumar; Siggs, Owen M.; Feng, Liang; Whisenhunt, Kristina N.; Yanovitch, Tammy L.; Kalaydjieva, Luba; Azmanov, Dimitar N.; Finzi, Simone; Tanna, Christine E.; Hewitt, Alex W.; Mackey, David A.; Bradfield, Yasmin S.; Souzeau, Emmanuelle; Javadiyan, Shari; Wiggs, Janey L.; Pasutto, Francesca; Liu, Xiaorong; John, Simon W.M.; Craig, Jamie E.; Jin, Jing; Young, Terri L.; Quaggin, Susan E.
In: Journal of Clinical Investigation, Vol. 127, No. 12, 01.12.2017, p. 4421-4436.Research output: Contribution to journal › Article
TY - JOUR
T1 - Angiopoietin-1 is required for Schlemm’s canal development in mice and humans
AU - Thomson, Benjamin R.
AU - Souma, Tomokazu
AU - Tompson, Stuart W.
AU - Onay, Tuncer
AU - Kizhatil, Krishnakumar
AU - Siggs, Owen M.
AU - Feng, Liang
AU - Whisenhunt, Kristina N.
AU - Yanovitch, Tammy L.
AU - Kalaydjieva, Luba
AU - Azmanov, Dimitar N.
AU - Finzi, Simone
AU - Tanna, Christine E.
AU - Hewitt, Alex W.
AU - Mackey, David A.
AU - Bradfield, Yasmin S.
AU - Souzeau, Emmanuelle
AU - Javadiyan, Shari
AU - Wiggs, Janey L.
AU - Pasutto, Francesca
AU - Liu, Xiaorong
AU - John, Simon W.M.
AU - Craig, Jamie E.
AU - Jin, Jing
AU - Young, Terri L.
AU - Quaggin, Susan E
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm’s canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
AB - Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm’s canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
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U2 - 10.1172/JCI95545
DO - 10.1172/JCI95545
M3 - Article
VL - 127
SP - 4421
EP - 4436
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -