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PITX2 gain-of-function in rieger syndrome eye model.

Holmberg, Johan LU ; Liu, Chia-Yang and Hjalt, Tord LU (2004) In American Journal of Pathology 165(5). p.1633-1641
Abstract
The human autosomal-dominant disorder Axenfeld-Rieger syndrome presents with defects in development of the eyes, teeth, and umbilicus. The eye manifests with iris ruptures, irido-corneal adhesions, cloudy corneas, and glaucoma. Transcription factors such as PITX2 and FOXC1 have been found to carry point mutations, causing the disorder. However, for approximately 40% of the cases, the pathogenesis is unknown. It has been reported that some mutations in PITX2 increase transactivation, whereas most mutations cause defects in DNA binding or transactivation. It is not known whether up-regulation of PITX2 activity can cause the disorder as well. Here we test this hypothesis directly by overexpressing PITX2A as a transgene in mouse corneal... (More)
The human autosomal-dominant disorder Axenfeld-Rieger syndrome presents with defects in development of the eyes, teeth, and umbilicus. The eye manifests with iris ruptures, irido-corneal adhesions, cloudy corneas, and glaucoma. Transcription factors such as PITX2 and FOXC1 have been found to carry point mutations, causing the disorder. However, for approximately 40% of the cases, the pathogenesis is unknown. It has been reported that some mutations in PITX2 increase transactivation, whereas most mutations cause defects in DNA binding or transactivation. It is not known whether up-regulation of PITX2 activity can cause the disorder as well. Here we test this hypothesis directly by overexpressing PITX2A as a transgene in mouse corneal mesenchyme and iris, using keratocan-flanking sequences. The mice presented with corneal opacification, corneal hypertrophy, irido-corneal adhesions, and severely degenerated retina, resembling glaucoma. The corneal hypertrophy also resembles the corneal hypertrophy of Pitx2-/- mice. Control transgenic mice carrying point mutations T68P or K88E in PITX2A were normal. These findings indicate a novel pathogenetic mechanism in which excess corneal and iridal PITX2A cause glaucoma and anterior defects that closely resemble Axenfeld-Rieger syndrome. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
165
issue
5
pages
1633 - 1641
publisher
American Society for Investigative Pathology
external identifiers
  • pmid:15509533
  • wos:000224736800018
  • scopus:7244227767
ISSN
1525-2191
DOI
10.1016/S0002-9440(10)63420-7
language
English
LU publication?
yes
id
13da450f-14fe-4544-87c1-21c1cbccdfdc (old id 131105)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15509533&dopt=Abstract
date added to LUP
2007-07-13 12:13:29
date last changed
2017-11-05 03:35:00
@article{13da450f-14fe-4544-87c1-21c1cbccdfdc,
  abstract     = {The human autosomal-dominant disorder Axenfeld-Rieger syndrome presents with defects in development of the eyes, teeth, and umbilicus. The eye manifests with iris ruptures, irido-corneal adhesions, cloudy corneas, and glaucoma. Transcription factors such as PITX2 and FOXC1 have been found to carry point mutations, causing the disorder. However, for approximately 40% of the cases, the pathogenesis is unknown. It has been reported that some mutations in PITX2 increase transactivation, whereas most mutations cause defects in DNA binding or transactivation. It is not known whether up-regulation of PITX2 activity can cause the disorder as well. Here we test this hypothesis directly by overexpressing PITX2A as a transgene in mouse corneal mesenchyme and iris, using keratocan-flanking sequences. The mice presented with corneal opacification, corneal hypertrophy, irido-corneal adhesions, and severely degenerated retina, resembling glaucoma. The corneal hypertrophy also resembles the corneal hypertrophy of Pitx2-/- mice. Control transgenic mice carrying point mutations T68P or K88E in PITX2A were normal. These findings indicate a novel pathogenetic mechanism in which excess corneal and iridal PITX2A cause glaucoma and anterior defects that closely resemble Axenfeld-Rieger syndrome.},
  author       = {Holmberg, Johan and Liu, Chia-Yang and Hjalt, Tord},
  issn         = {1525-2191},
  language     = {eng},
  number       = {5},
  pages        = {1633--1641},
  publisher    = {American Society for Investigative Pathology},
  series       = {American Journal of Pathology},
  title        = {PITX2 gain-of-function in rieger syndrome eye model.},
  url          = {http://dx.doi.org/10.1016/S0002-9440(10)63420-7},
  volume       = {165},
  year         = {2004},
}