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PITX2 gain-of-function in Axenfeld-Rieger eye model.

Hjalt, Tord LU ; Holmberg, Johan LU and Liu, C-Y (2004) American Society of Human Genetics
Abstract
The Axenfeld-Rieger syndrome is autosomal dominant and affects the development of eyes, teeth, and gut. The eye
manifestations include cloudy corneas, tearing, glaucoma, iris hypoplasia, irido-corneal adhesion, and occasionally
megalocornea. Mutations have been found in the genes for transcription factors PITX2 and FOXC1. Mice homozygous
for disruption of PITX2 are embryonic lethal from heart malformation. These mice also have hypertrophic corneas.
Most mutations found in humans are defective in either DNA binding or reporter gene transactivation in cell culture.
One mutation previously studied exhibited increased transactivation. Another has been shown to be dominant negative.
Here we have made a transgenic mouse... (More)
The Axenfeld-Rieger syndrome is autosomal dominant and affects the development of eyes, teeth, and gut. The eye
manifestations include cloudy corneas, tearing, glaucoma, iris hypoplasia, irido-corneal adhesion, and occasionally
megalocornea. Mutations have been found in the genes for transcription factors PITX2 and FOXC1. Mice homozygous
for disruption of PITX2 are embryonic lethal from heart malformation. These mice also have hypertrophic corneas.
Most mutations found in humans are defective in either DNA binding or reporter gene transactivation in cell culture.
One mutation previously studied exhibited increased transactivation. Another has been shown to be dominant negative.
Here we have made a transgenic mouse model, overexpressing normal human PITX2A in the cornea. These mice
present with cloudy corneas, tearing, irido-corneal adhesions, mild to severe corneal hypertrophy and severe progressive
retinal degradation. The corneal collagen superstructure is disrupted. Proposed PITX2 target gene procollagen lysyl
hydroxylase 2 (Plod2) is down-regulated by whole eye RTPCR. The proposed cardiac PITX2 target gene cyclin D2 is
not affected. This model provides in vivo evidence for a gain-of-function pathology for PITX2 causing Axenfeld-
Rieger-like eye symptoms. In addition to the eye phenotypes, there is a random left-right forelimb malformation. The
radius is curved over the ulna, locking the elbow in a pronation-extension position. (Less)
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published
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conference name
American Society of Human Genetics
conference location
Toronto, Canada
conference dates
2025-10-27
language
English
LU publication?
yes
id
7ae80ba0-9541-4255-be5a-2d01f9bd1b13
alternative location
https://www.ashg.org/wp-content/uploads/2019/10/2004-poster-abstracts.pdf
date added to LUP
2024-12-10 10:25:23
date last changed
2025-04-04 14:59:43
@misc{7ae80ba0-9541-4255-be5a-2d01f9bd1b13,
  abstract     = {{The Axenfeld-Rieger syndrome is autosomal dominant and affects the development of eyes, teeth, and gut. The eye<br/>manifestations include cloudy corneas, tearing, glaucoma, iris hypoplasia, irido-corneal adhesion, and occasionally<br/>megalocornea. Mutations have been found in the genes for transcription factors PITX2 and FOXC1. Mice homozygous<br/>for disruption of PITX2 are embryonic lethal from heart malformation. These mice also have hypertrophic corneas.<br/>Most mutations found in humans are defective in either DNA binding or reporter gene transactivation in cell culture.<br/>One mutation previously studied exhibited increased transactivation. Another has been shown to be dominant negative.<br/>Here we have made a transgenic mouse model, overexpressing normal human PITX2A in the cornea. These mice<br/>present with cloudy corneas, tearing, irido-corneal adhesions, mild to severe corneal hypertrophy and severe progressive<br/>retinal degradation. The corneal collagen superstructure is disrupted. Proposed PITX2 target gene procollagen lysyl<br/>hydroxylase 2 (Plod2) is down-regulated by whole eye RTPCR. The proposed cardiac PITX2 target gene cyclin D2 is<br/>not affected. This model provides in vivo evidence for a gain-of-function pathology for PITX2 causing Axenfeld-<br/>Rieger-like eye symptoms. In addition to the eye phenotypes, there is a random left-right forelimb malformation. The<br/>radius is curved over the ulna, locking the elbow in a pronation-extension position.}},
  author       = {{Hjalt, Tord and Holmberg, Johan and Liu, C-Y}},
  language     = {{eng}},
  title        = {{PITX2 gain-of-function in Axenfeld-Rieger eye model.}},
  url          = {{https://www.ashg.org/wp-content/uploads/2019/10/2004-poster-abstracts.pdf}},
  year         = {{2004}},
}