Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development

Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. To identify new disease genes, we performed whole-exome sequencing of 26 unrelated CG patients. In one patient we identified two rare, recessiv...

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Autores: Ferré Fernández, Jesús José, Aroca Aguilar, José Daniel, Medina Trillo, Cristina, Bonet Fernández, Juan Manuel, Méndez Hernández, Carmen Dora, Morales Fernández, Laura, Cortón, Marta, Cabañero Valera, María José, Gut, Marta, Tonda, Raúl, Ayuso, Carmen, Coca Prados, Miguel, García Feijóo, Julián, Escribano, Julio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/35207
Acceso en línea:http://hdl.handle.net/10230/35207
http://dx.doi.org/10.1038/srep46175
Access Level:acceso abierto
Palabra clave:GPATCH3 gene
Whole exome sequencing
Craniofacial abnormalities
Congenital glaucoma
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spelling Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial developmentFerré Fernández, Jesús JoséAroca Aguilar, José DanielMedina Trillo, CristinaBonet Fernández, Juan ManuelMéndez Hernández, Carmen DoraMorales Fernández, LauraCortón, MartaCabañero Valera, María JoséGut, MartaTonda, RaúlAyuso, CarmenCoca Prados, MiguelGarcía Feijóo, JuliánEscribano, JulioGPATCH3 geneWhole exome sequencingCraniofacial abnormalitiesCongenital glaucomaCongenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. To identify new disease genes, we performed whole-exome sequencing of 26 unrelated CG patients. In one patient we identified two rare, recessive and hypermorphic coding variants in GPATCH3, a gene of unidentified function, and 5% of a second group of 170 unrelated CG patients carried rare variants in this gene. The recombinant GPATCH3 protein activated in vitro the proximal promoter of CXCR4, a gene involved in embryo neural crest cell migration. The GPATCH3 protein was detected in human tissues relevant to glaucoma (e.g., ciliary body). This gene was expressed in the dermis, skeletal muscles, periocular mesenchymal-like cells and corneal endothelium of early zebrafish embryos. Morpholino-mediated knockdown and transient overexpression of gpatch3 led to varying degrees of goniodysgenesis and ocular and craniofacial abnormalities, recapitulating some of the features of zebrafish embryos deficient in the glaucoma-related genes pitx2 and foxc1. In conclusion, our data suggest the existence of high genetic heterogeneity in CG and provide evidence for the role of GPATCH3 in this disease. We also show that GPATCH3 is a new gene involved in ocular and craniofacial development.This study has been supported by research grants from the “Instituto de Salud Carlos III/FEDER” (RD12/0034/0003, PI11/00662, PI15/01193 to JE and CP12/03256 to MC), the Ministry of Economy and Competitiveness/FEDER (MINECO, SAF2013-46943-R to MC and PT13/0001/0044 to MG), Mutua Madrileña Foundation (to MC), and the Regional Ministry of Science and Technology of the Board of the Communities of “Castilla-La Mancha” (PEII-2014-002-P to JE). Jesús-José Ferre-Fernández is the recipient of a predoctoral fellowship from the “Instituto de Salud Carlos III” (FI12/00287). Miguel Coca-Prados is “Catedrático Rafael del Pino en Oftalmología” in the “Fundación de Investigación Oftalmológica, Instituto Oftalmológico Fernández-Vega” Oviedo, Spain. Marta Corton is sponsored by the Miguel Servet Program (CP12/03256) from Instituto de Salud Carlos III/FEDER).Nature Publishing Group201820182017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/35207http://dx.doi.org/10.1038/srep46175reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésScientific Reports. 2017 Apr 11;7:46175info:eu-repo/grantAgreement/ES/1PE/SAF2013-46943-R© The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/352072026-05-29T05:05:01Z
dc.title.none.fl_str_mv Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
title Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
spellingShingle Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
Ferré Fernández, Jesús José
GPATCH3 gene
Whole exome sequencing
Craniofacial abnormalities
Congenital glaucoma
title_short Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
title_full Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
title_fullStr Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
title_full_unstemmed Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
title_sort Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
dc.creator.none.fl_str_mv Ferré Fernández, Jesús José
Aroca Aguilar, José Daniel
Medina Trillo, Cristina
Bonet Fernández, Juan Manuel
Méndez Hernández, Carmen Dora
Morales Fernández, Laura
Cortón, Marta
Cabañero Valera, María José
Gut, Marta
Tonda, Raúl
Ayuso, Carmen
Coca Prados, Miguel
García Feijóo, Julián
Escribano, Julio
author Ferré Fernández, Jesús José
author_facet Ferré Fernández, Jesús José
Aroca Aguilar, José Daniel
Medina Trillo, Cristina
Bonet Fernández, Juan Manuel
Méndez Hernández, Carmen Dora
Morales Fernández, Laura
Cortón, Marta
Cabañero Valera, María José
Gut, Marta
Tonda, Raúl
Ayuso, Carmen
Coca Prados, Miguel
García Feijóo, Julián
Escribano, Julio
author_role author
author2 Aroca Aguilar, José Daniel
Medina Trillo, Cristina
Bonet Fernández, Juan Manuel
Méndez Hernández, Carmen Dora
Morales Fernández, Laura
Cortón, Marta
Cabañero Valera, María José
Gut, Marta
Tonda, Raúl
Ayuso, Carmen
Coca Prados, Miguel
García Feijóo, Julián
Escribano, Julio
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GPATCH3 gene
Whole exome sequencing
Craniofacial abnormalities
Congenital glaucoma
topic GPATCH3 gene
Whole exome sequencing
Craniofacial abnormalities
Congenital glaucoma
description Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. To identify new disease genes, we performed whole-exome sequencing of 26 unrelated CG patients. In one patient we identified two rare, recessive and hypermorphic coding variants in GPATCH3, a gene of unidentified function, and 5% of a second group of 170 unrelated CG patients carried rare variants in this gene. The recombinant GPATCH3 protein activated in vitro the proximal promoter of CXCR4, a gene involved in embryo neural crest cell migration. The GPATCH3 protein was detected in human tissues relevant to glaucoma (e.g., ciliary body). This gene was expressed in the dermis, skeletal muscles, periocular mesenchymal-like cells and corneal endothelium of early zebrafish embryos. Morpholino-mediated knockdown and transient overexpression of gpatch3 led to varying degrees of goniodysgenesis and ocular and craniofacial abnormalities, recapitulating some of the features of zebrafish embryos deficient in the glaucoma-related genes pitx2 and foxc1. In conclusion, our data suggest the existence of high genetic heterogeneity in CG and provide evidence for the role of GPATCH3 in this disease. We also show that GPATCH3 is a new gene involved in ocular and craniofacial development.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/35207
http://dx.doi.org/10.1038/srep46175
url http://hdl.handle.net/10230/35207
http://dx.doi.org/10.1038/srep46175
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Scientific Reports. 2017 Apr 11;7:46175
info:eu-repo/grantAgreement/ES/1PE/SAF2013-46943-R
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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