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A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis

Glaucoma is a leading cause of blindness, affecting 70 million people worldwide. Owing to the similarity in anatomy and physiology between human and mouse eyes and the ability to genetically manipulate mice, mouse models are an invaluable resource for studying mechanisms underlying disease phenotype...

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Autores principales: Yang, Yeming, Li, Xiao, Wang, Jieping, Tan, Junkai, Fitzmaurice, Bernie, Nishina, Patsy M., Sun, Kuanxiang, Tian, Wanli, Liu, Wenjing, Liu, Xuyang, Chang, Bo, Zhu, Xianjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556256/
https://www.ncbi.nlm.nih.gov/pubmed/34716303
http://dx.doi.org/10.1038/s41419-021-04331-1
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author Yang, Yeming
Li, Xiao
Wang, Jieping
Tan, Junkai
Fitzmaurice, Bernie
Nishina, Patsy M.
Sun, Kuanxiang
Tian, Wanli
Liu, Wenjing
Liu, Xuyang
Chang, Bo
Zhu, Xianjun
author_facet Yang, Yeming
Li, Xiao
Wang, Jieping
Tan, Junkai
Fitzmaurice, Bernie
Nishina, Patsy M.
Sun, Kuanxiang
Tian, Wanli
Liu, Wenjing
Liu, Xuyang
Chang, Bo
Zhu, Xianjun
author_sort Yang, Yeming
collection PubMed
description Glaucoma is a leading cause of blindness, affecting 70 million people worldwide. Owing to the similarity in anatomy and physiology between human and mouse eyes and the ability to genetically manipulate mice, mouse models are an invaluable resource for studying mechanisms underlying disease phenotypes and for developing therapeutic strategies. Here, we report the discovery of a new mouse model of early-onset glaucoma that bears a transversion substitution c. G344T, which results in a missense mutation, p. R115L in PITX2. The mutation causes an elevation in intraocular pressure (IOP) and progressive death of retinal ganglion cells (RGC). These ocular phenotypes recapitulate features of pathologies observed in human glaucoma. Increased oxidative stress was evident in the inner retina. We demonstrate that the mutant PITX2 protein was not capable of binding to Nuclear factor-like 2 (NRF2), which regulates Pitx2 expression and nuclear localization, and to YAP1, which is necessary for co-initiation of transcription of downstream targets. PITX2-mediated transcription of several antioxidant genes were also impaired. Treatment with N-Acetyl-L-cysteine exerted a profound neuroprotective effect on glaucoma-associated neuropathies, presumably through inhibition of oxidative stress. Our study demonstrates that a disruption of PITX2 leads to glaucoma optic pathogenesis and provides a novel early-onset glaucoma model that will enable elucidation of mechanisms underlying the disease as well as to serve as a resource to test new therapeutic strategies.
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spelling pubmed-85562562021-11-15 A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis Yang, Yeming Li, Xiao Wang, Jieping Tan, Junkai Fitzmaurice, Bernie Nishina, Patsy M. Sun, Kuanxiang Tian, Wanli Liu, Wenjing Liu, Xuyang Chang, Bo Zhu, Xianjun Cell Death Dis Article Glaucoma is a leading cause of blindness, affecting 70 million people worldwide. Owing to the similarity in anatomy and physiology between human and mouse eyes and the ability to genetically manipulate mice, mouse models are an invaluable resource for studying mechanisms underlying disease phenotypes and for developing therapeutic strategies. Here, we report the discovery of a new mouse model of early-onset glaucoma that bears a transversion substitution c. G344T, which results in a missense mutation, p. R115L in PITX2. The mutation causes an elevation in intraocular pressure (IOP) and progressive death of retinal ganglion cells (RGC). These ocular phenotypes recapitulate features of pathologies observed in human glaucoma. Increased oxidative stress was evident in the inner retina. We demonstrate that the mutant PITX2 protein was not capable of binding to Nuclear factor-like 2 (NRF2), which regulates Pitx2 expression and nuclear localization, and to YAP1, which is necessary for co-initiation of transcription of downstream targets. PITX2-mediated transcription of several antioxidant genes were also impaired. Treatment with N-Acetyl-L-cysteine exerted a profound neuroprotective effect on glaucoma-associated neuropathies, presumably through inhibition of oxidative stress. Our study demonstrates that a disruption of PITX2 leads to glaucoma optic pathogenesis and provides a novel early-onset glaucoma model that will enable elucidation of mechanisms underlying the disease as well as to serve as a resource to test new therapeutic strategies. Nature Publishing Group UK 2021-10-29 /pmc/articles/PMC8556256/ /pubmed/34716303 http://dx.doi.org/10.1038/s41419-021-04331-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Yang, Yeming
Li, Xiao
Wang, Jieping
Tan, Junkai
Fitzmaurice, Bernie
Nishina, Patsy M.
Sun, Kuanxiang
Tian, Wanli
Liu, Wenjing
Liu, Xuyang
Chang, Bo
Zhu, Xianjun
A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis
title A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis
title_full A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis
title_fullStr A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis
title_full_unstemmed A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis
title_short A missense mutation in Pitx2 leads to early-onset glaucoma via NRF2-YAP1 axis
title_sort missense mutation in pitx2 leads to early-onset glaucoma via nrf2-yap1 axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556256/
https://www.ncbi.nlm.nih.gov/pubmed/34716303
http://dx.doi.org/10.1038/s41419-021-04331-1
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