title: Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development.
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.
authors.affiliation: Área de Genética, Facultad de Medicina/Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Jesús-José
authors.initials: JJ
authors.lastname: Ferre-Fernández
authors.affiliation: 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.
authors.forename: José-Daniel
authors.initials: JD
authors.lastname: Aroca-Aguilar
authors.affiliation: 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.
authors.forename: Cristina
authors.initials: C
authors.lastname: Medina-Trillo
authors.affiliation: 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.
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Bonet-Fernández
authors.affiliation: 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.
authors.forename: Carmen-Dora
authors.initials: CD
authors.lastname: Méndez-Hernández
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Morales-Fernández
authors.affiliation: 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.
authors.forename: Marta
authors.initials: M
authors.lastname: Corton
authors.affiliation: 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.
authors.forename: María-José
authors.initials: MJ
authors.lastname: Cabañero-Valera
authors.affiliation: 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.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: 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.
authors.forename: Raul
authors.initials: R
authors.lastname: Tonda
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.affiliation: 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.
authors.forename: Miguel
authors.initials: M
authors.lastname: Coca-Prados
authors.affiliation: 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.
authors.forename: Julián
authors.initials: J
authors.lastname: García-Feijoo
authors.affiliation: 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.
authors.forename: Julio
authors.initials: J
authors.lastname: Escribano
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D020090:Chromosome Segregation / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005123:Eye / Q000196:embryology*; D005145:Face / Q000196:embryology*; D005190:Family; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D012886:Skull / Q000196:embryology*; D013347:Subcellular Fractions / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D000073359:Exome Sequencing; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: C527276:CXCR4 protein, human; D002352:Carrier Proteins; C000621579:GPATCH3 protein, human; D019718:Receptors, CXCR4