Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma

Abstract

The human eye is a complex organ whose development requires extraordinary coordination of developmental processes. The conservation of ocular developmental steps in vertebrates suggests possible common genetic mechanisms. Genetic diseases involving the eye represent a leading cause of blindness in children and adults. During the last decades, there has been an exponential increase in genetic studies of ocular disorders. In this review, we summarize current success in identification of genes responsible for microphthalmia, anophthalmia, and coloboma (MAC) phenotypes, which are associated with early defects in embryonic eye development. Studies in animal models for the orthologous genes identified overlapping phenotypes for most factors, confirming the conservation of their function in vertebrate development. These animal models allow for further investigation of the mechanisms of MAC, integration of various identified genes into common developmental pathways and finally, provide an avenue for the development and testing of therapeutic interventions.

Keywords: animal models; anophthalmia; coloboma; eye development; genetics; microphthalmia.

Figure 1

Schematic drawing of vertebrate ocular development. (A) Optic vesicle formation as an evagination from the diencephalon. (B) Following close contact with the surface ectoderm, the optic vesicle becomes divided into presumptive RPE, neural retina, and optic stalk, while the surface ectoderm in induced to form the lens placode. (C, D) The optic vesicle and lens placode co-invaginate, giving rise to the bilayered optic cup and the lens vesicle, respectively. (E) The lens differentiates to form the primary lens fibers (posterior) and the lens epithelium (anterior); the neural retina and the pigment epithelium continue to develop; the optic stalk gives rise to the optic nerve; the surface ectoderm adjacent to the lens gives rise to the corneal epithelium. Abbreviations: C: Cornea; L: lens; LP: lens placode; LV: lens vesicle; MS: mesenchyme; NR: neural retina; ON: optic nerve; OS: optic stalk; OV: optic vesicle; RPE: retinal pigment epithelium; S: sclera; SE: surface ectoderm. Modified from Adler and Canto-Soler with permission (Adler and Canto-Soler, 2007).

Figure 2

Images of MAC patients with different genetic mutations. Images of patients affected with SOX2 (A–C), FOXE3 (D) and BMP4 (E–G) mutations. Of note, some patients have prosthetic eyes in place. Images A–B, E–G are reproduced with permission from (Reis et al., 2011; Schneider et al., 2009).