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Open AccessArticle

Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish

Área de Genética, Facultad de Medicina de Albacete/Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, 02006 Albacete, Spain
Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality (OFTARED), Instituto de Salud Carlos III, 28029 Madrid, Spain
Servicio de Oftalmología, Hospital San Carlos, 28040 Madrid, Spain
Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, 28040 Madrid, Spain
Department of Optics, Pharmacology and Anatomy, University of Alicante, 03690 Alicante, Spain
Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06510, USA
Author to whom correspondence should be addressed.
Genes 2020, 11(5), 550;
Received: 27 March 2020 / Revised: 6 May 2020 / Accepted: 12 May 2020 / Published: 14 May 2020
(This article belongs to the Special Issue Molecular Genetics of Retinal Dystrophies)
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. View Full-Text
Keywords: primary congenital glaucoma; exome sequencing; GUCA1C; GCAP3; zebrafish; CRISPR/Cas9 primary congenital glaucoma; exome sequencing; GUCA1C; GCAP3; zebrafish; CRISPR/Cas9
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Morales-Cámara, S.; Alexandre-Moreno, S.; Bonet-Fernández, J.-M.; Atienzar-Aroca, R.; Aroca-Aguilar, J.-D.; Ferre-Fernández, J.-J.; Méndez, C.-D.; Morales, L.; Fernández-Sánchez, L.; Cuenca, N.; Coca-Prados, M.; Martínez-de-la-Casa, J.-M.; Garcia-Feijoo, J.; Escribano, J. Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish. Genes 2020, 11, 550.

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