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; 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

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

Full item page Simple item page

dc.contributor.author Ferré Fernández, Jesús Joséca
dc.contributor.author Aroca Aguilar, José Danielca
dc.contributor.author Medina Trillo, Cristinaca
dc.contributor.author Bonet Fernández, Juan Manuelca
dc.contributor.author Méndez Hernández, Carmen Doraca
dc.contributor.author Morales Fernández, Lauraca
dc.contributor.author Cortón, Martaca
dc.contributor.author Cabañero Valera, María Joséca
dc.contributor.author Gut, Martaca
dc.contributor.author Tonda, Raúlca
dc.contributor.author Ayuso, Carmenca
dc.contributor.author Coca Prados, Miguelca
dc.contributor.author García Feijóo, Juliánca
dc.contributor.author Escribano, Julioca
dc.date.accessioned 2018-07-20T07:34:25Z
dc.date.available 2018-07-20T07:34:25Z
dc.date.issued 2017
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.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.doi http://dx.doi.org/10.1038/srep46175
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/35207
dc.language.iso eng
dc.publisher Nature Publishing Groupca
dc.relation.ispartof Scientific Reports. 2017 Apr 11;7:46175
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-46943-R
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.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword GPATCH3 gene
dc.subject.keyword Whole exome sequencing
dc.subject.keyword Craniofacial abnormalities
dc.subject.keyword Congenital glaucoma
dc.title Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial developmentca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

Collections

Articles (Center for Genomic Regulation (CRG))
Articles (Departament de Medicina i Ciències de la Vida)