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Sci Rep. 2017 Apr 11;7:46175. doi: 10.1038/srep46175.

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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Área de Genética, Facultad de Medicina/Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain.
Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality, Instituto de Salud Carlos III, Madrid, Spain.
Servicio de Oftalmología, Hospital San Carlos, Madrid, Spain/Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
Área de Genética &Genómica, Instituto de Investigación Sanitaria-Hospital Universitario Fundación Jiménez Díaz-Universidad Autónoma de Madrid (IIS-FJD, UAM)/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
CNAG-CRG, Centre for Genomic Regulation (CRG), Institute of Science and Technology (BIST), Centre for Genomic Analysis (CNAG), Barcelona, Spain.
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Fundación de Investigación Oftalmológica, Instituto Oftalmológico Fernandez-Vega, Oviedo, Spain.
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT, USA.


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.

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