Abstract
Ocular morphogenesis in vertebrates is a highly organized process, orchestrated largely by intrinsic genetic programs that exhibit stringent spatiotemporal control. Alternations in these genetic instructions can lead to hereditary or nonhereditary congenital disorders, a major cause of childhood visual impairment, and contribute to common late-onset blinding diseases. Currently, limited treatment options exist for clinical phenotypes involving eye development. This review summarizes recent advances in our understanding of early-onset ocular disorders and highlights genetic complexities in development and diseases, specifically focusing on coloboma, congenital glaucoma and Leber congenital amaurosis. We also discuss innovative paradigms for potential therapeutic modalities.
Highlights
Amongst the plethora of ocular disorders, congenital anomalies and early-onset diseases have particular significance
Exhibiting some common etiologies with coloboma, congenital glaucoma can be caused by alteration of transcription factors or signaling pathways crucial for the development of the anterior segment
Prevention of colobomata requires the identification of disease-causing genetic profiles and their precise correction before the initiation of the optic fissure closure at gestation week 16; such corrections are not feasible currently since tissue regeneration would be required at an unprecedented scale, with existing stem cells coaxed into repopulating the affected area
Summary
Amongst the plethora of ocular disorders, congenital anomalies and early-onset diseases have particular significance. Extensive remodeling is required for the optic cup to form an intact spherical globe, a process that involves closure of a large fissure on the ventral or inferior portion of the eye Failure of this choroid fissure to close results in coloboma (plural colobomata) À a spectrum of pediatric defects and malformations that represent important causes of visual impairment and blindness. Perturbation of neural crest function results in optic fissure closure defects [5,6] as well as diverse congenital ocular diseases, including Axenfeld-Rieger syndrome and congenital glaucoma Another key facet of ocular development concerns the processes by which retinal progenitor cells (RPCs), derived from neuroepithelium of the optic cup, form six distinct neuronal cell types and one type of glia in an ordered and overlapping sequence (Fig. 1B and 1C). Identification of disease-causing genes and elucidation of respective pathogenic mechanisms offer opportunities for developing novel treatment modalities
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