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.
Highlights
Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye
Among an average of 60 variants located in well-supported transcripts per subject, we selected as candidates two GPATCH3 (G-PATCH DOMAIN-CONTAINING PROTEIN 3) variants present in patient primary congenital glaucoma (PCG)-99 (Fig. 1B)
Given the possibility of high locus heterogeneity among this group of patients and based on the idea that PCG results from maldevelopment of the aqueous outflow system, we focused our search on private variants of genes potentially involved in ocular development, many of which regulate gene expression
Summary
Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. The pathogenesis of PCG remains uncertain but it is thought to originate from the isolated maldevelopment of structures in the anterior segment of the eye due to arrested maturation of tissues derived from cranial neural crest cells[3,4] This anomaly leads to decreased aqueous humor outflow. Even among the cases with null enzymatic activity, remarkable phenotypic variation is present[6,7,15] These facts, along with the existence of incomplete penetrance and the discovery of a significant proportion of patients who carry non-dominant heterozygous CYP1B1 mutations[6], suggest that more than one gene is involved in PCG. Our results suggest the existence of remarkable genetic heterogeneity in congenital glaucoma and provide evidence for the role of GPATCH3 in this disease. We show that GPATCH3 is a new gene involved in ocular and craniofacial development
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