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Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish

Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1...

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Autores principales: Morales-Cámara, Samuel, Alexandre-Moreno, Susana, Bonet-Fernández, Juan-Manuel, Atienzar-Aroca, Raquel, Aroca-Aguilar, José-Daniel, Ferre-Fernández, Jesús-José, Méndez, Carmen-Dora, Morales, Laura, Fernández-Sánchez, Laura, Cuenca, Nicolas, Coca-Prados, Miguel, Martínez-de-la-Casa, José-María, Garcia-Feijoo, Julián, Escribano, Julio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288452/
https://www.ncbi.nlm.nih.gov/pubmed/32422965
http://dx.doi.org/10.3390/genes11050550
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author Morales-Cámara, Samuel
Alexandre-Moreno, Susana
Bonet-Fernández, Juan-Manuel
Atienzar-Aroca, Raquel
Aroca-Aguilar, José-Daniel
Ferre-Fernández, Jesús-José
Méndez, Carmen-Dora
Morales, Laura
Fernández-Sánchez, Laura
Cuenca, Nicolas
Coca-Prados, Miguel
Martínez-de-la-Casa, José-María
Garcia-Feijoo, Julián
Escribano, Julio
author_facet Morales-Cámara, Samuel
Alexandre-Moreno, Susana
Bonet-Fernández, Juan-Manuel
Atienzar-Aroca, Raquel
Aroca-Aguilar, José-Daniel
Ferre-Fernández, Jesús-José
Méndez, Carmen-Dora
Morales, Laura
Fernández-Sánchez, Laura
Cuenca, Nicolas
Coca-Prados, Miguel
Martínez-de-la-Casa, José-María
Garcia-Feijoo, Julián
Escribano, Julio
author_sort Morales-Cámara, Samuel
collection PubMed
description Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G > T/p.Glu18Ter/rs143174402). This gene encodes GCAP3, a member of the guanylate cyclase activating protein family, involved in phototransduction and with a potential role in intraocular pressure regulation. Segregation analysis supported the notion that the variant was coinherited with the disease in an autosomal recessive fashion. GCAP3 was detected immunohistochemically in the adult human ocular ciliary epithelium and retina. To evaluate the ocular effect of GUCA1C loss-of-function, a guca1c knockout zebrafish line was generated by CRISPR/Cas9 genome editing. Immunohistochemistry demonstrated the presence of GCAP3 in the non-pigmented ciliary epithelium and retina of adult wild-type fishes. Knockout animals presented up-regulation of the glial fibrillary acidic protein in Müller cells and evidence of retinal ganglion cell apoptosis, indicating the existence of gliosis and glaucoma-like retinal damage. In summary, our data provide evidence for the role of GUCA1C as a candidate gene in PCG and offer new insights into the function of this gene in the ocular anterior segment and the retina.
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spelling pubmed-72884522020-06-17 Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish Morales-Cámara, Samuel Alexandre-Moreno, Susana Bonet-Fernández, Juan-Manuel Atienzar-Aroca, Raquel Aroca-Aguilar, José-Daniel Ferre-Fernández, Jesús-José Méndez, Carmen-Dora Morales, Laura Fernández-Sánchez, Laura Cuenca, Nicolas Coca-Prados, Miguel Martínez-de-la-Casa, José-María Garcia-Feijoo, Julián Escribano, Julio Genes (Basel) Article Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G > T/p.Glu18Ter/rs143174402). This gene encodes GCAP3, a member of the guanylate cyclase activating protein family, involved in phototransduction and with a potential role in intraocular pressure regulation. Segregation analysis supported the notion that the variant was coinherited with the disease in an autosomal recessive fashion. GCAP3 was detected immunohistochemically in the adult human ocular ciliary epithelium and retina. To evaluate the ocular effect of GUCA1C loss-of-function, a guca1c knockout zebrafish line was generated by CRISPR/Cas9 genome editing. Immunohistochemistry demonstrated the presence of GCAP3 in the non-pigmented ciliary epithelium and retina of adult wild-type fishes. Knockout animals presented up-regulation of the glial fibrillary acidic protein in Müller cells and evidence of retinal ganglion cell apoptosis, indicating the existence of gliosis and glaucoma-like retinal damage. In summary, our data provide evidence for the role of GUCA1C as a candidate gene in PCG and offer new insights into the function of this gene in the ocular anterior segment and the retina. MDPI 2020-05-14 /pmc/articles/PMC7288452/ /pubmed/32422965 http://dx.doi.org/10.3390/genes11050550 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Morales-Cámara, Samuel
Alexandre-Moreno, Susana
Bonet-Fernández, Juan-Manuel
Atienzar-Aroca, Raquel
Aroca-Aguilar, José-Daniel
Ferre-Fernández, Jesús-José
Méndez, Carmen-Dora
Morales, Laura
Fernández-Sánchez, Laura
Cuenca, Nicolas
Coca-Prados, Miguel
Martínez-de-la-Casa, José-María
Garcia-Feijoo, Julián
Escribano, Julio
Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish
title Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish
title_full Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish
title_fullStr Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish
title_full_unstemmed Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish
title_short Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish
title_sort role of guca1c in primary congenital glaucoma and in the retina: functional evaluation in zebrafish
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288452/
https://www.ncbi.nlm.nih.gov/pubmed/32422965
http://dx.doi.org/10.3390/genes11050550
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