2026-04-13T04:57:48Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/352072025-12-12T03:19:03Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Ferré Fernández, Jesús José author Aroca Aguilar, José Daniel author Medina Trillo, Cristina author Bonet Fernández, Juan Manuel author Méndez Hernández, Carmen Dora author Morales Fernández, Laura author Cortón, Marta author Cabañero Valera, María José author Gut, Marta author Tonda, Raúl author Ayuso, Carmen author Coca Prados, Miguel author García Feijóo, Julián author Escribano, Julio author 2018-07-20T07:34:25Z 2018-07-20T07:34:25Z 2017 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. 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). GPATCH3 gene Whole exome sequencing Craniofacial abnormalities Congenital glaucoma Whole-exome sequencing of congenital glaucoma patients reveals hypermorphic variants in GPATCH3, a new gene involved in ocular and craniofacial development