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

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dc.contributor.author Ferré Fernández, Jesús José
dc.contributor.author Aroca Aguilar, José Daniel
dc.contributor.author Medina Trillo, Cristina
dc.contributor.author Bonet Fernández, Juan Manuel
dc.contributor.author Méndez Hernández, Carmen Dora
dc.contributor.author Morales Fernández, Laura
dc.contributor.author Cortón, Marta
dc.contributor.author Cabañero Valera, María José
dc.contributor.author Gut, Marta
dc.contributor.author Tonda, Raúl
dc.contributor.author Ayuso, Carmen
dc.contributor.author Coca Prados, Miguel
dc.contributor.author García Feijóo, Julián
dc.contributor.author Escribano, Julio
dc.date.accessioned 2018-07-20T07:34:25Z
dc.date.available 2018-07-20T07:34:25Z
dc.date.issued 2017
dc.identifier.citation Ferre-Fernández JJ, Aroca-Aguilar JD, Medina-Trillo C, Bonet-Fernández JM, Méndez-Hernández CD, Morales-Fernández L et al. Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development. Sci Rep. 2017 Apr 11;7:46175. DOI: 10.1038/srep46175
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/35207
dc.description.abstract 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.
dc.description.sponsorship 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).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Publishing Group
dc.relation.ispartof Scientific Reports. 2017 Apr 11;7:46175
dc.rights © 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/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/srep46175
dc.subject.keyword GPATCH3 gene
dc.subject.keyword Whole exome sequencing
dc.subject.keyword Craniofacial abnormalities
dc.subject.keyword Congenital glaucoma
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-46943-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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