Abstract
Primary congenital glaucoma (PCG) is a heterogeneous, inherited, and severe optical neuropathy caused by apoptotic degeneration of the retinal ganglion cell layer. Whole-exome sequencing analysis of one PCG family identified two affected siblings who carried a low-frequency homozygous nonsense GUCA1C variant (c.52G > T/p.Glu18Ter/rs143174402). This gene encodes GCAP3, a member of the guanylate cyclase activating protein family, involved in phototransduction and with a potential role in intraocular pressure regulation. Segregation analysis supported the notion that the variant was coinherited with the disease in an autosomal recessive fashion. GCAP3 was detected immunohistochemically in the adult human ocular ciliary epithelium and retina. To evaluate the ocular effect of GUCA1C loss-of-function, a guca1c knockout zebrafish line was generated by CRISPR/Cas9 genome editing. Immunohistochemistry demonstrated the presence of GCAP3 in the non-pigmented ciliary epithelium and retina of adult wild-type fishes. Knockout animals presented up-regulation of the glial fibrillary acidic protein in Müller cells and evidence of retinal ganglion cell apoptosis, indicating the existence of gliosis and glaucoma-like retinal damage. In summary, our data provide evidence for the role of GUCA1C as a candidate gene in PCG and offer new insights into the function of this gene in the ocular anterior segment and the retina.
Highlights
Glaucoma is a heterogeneous group of progressive and irreversible optic neuropathies stemming from the apoptotic death of retinal ganglion cells
This study is an extension of our previous WES analysis of 26 severe Primary congenital glaucoma (PCG) cases diagnosed before the fourth month of life, that were ruled out as carrying CYP1B1 alterations, and for which we reported no shared disease-causing genetic alterations [14]
We designed a variant filtering algorithm aimed at identifying rare coding variants with predicted moderate or high functional impact with recessive inheritance and shared by the two PCG siblings. This filtering pipeline identified only one homozygous nucleotide substitution in the GUANYLATE CYCLASE ACTIVATOR 1C (GUCA1C) gene (c.52G > T), predicted to result in a nonsense variant (p.(Glu18Ter), Figure 1A) that likely leads to the complete LoF of the gene product
Summary
Glaucoma is a heterogeneous group of progressive and irreversible optic neuropathies stemming from the apoptotic death of retinal ganglion cells It results in characteristic visual field loss. Arrested maturation of tissues derived from cranial neural crest cells is believed to underlie this disease This alteration results in increased aqueous humor (AH) outflow resistance, elevated intraocular pressure (IOP), and optic nerve degeneration and usually manifests in the form of the classic triad of tearing, photophobia and corneal clouding. The first identified and most prevalent cause of this type of inheritance is loss-of-function (LoF) of the CYP1B1 (CYTOCHROME P450, SUBFAMILY I, POLYPEPTIDE 1, MIM# 601771) gene [5], which is present in 18–48% of non-consanguineous European patients [6,7].
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