The regulation of cell division, growth, migration, programmed death, and differentiation, necessary for the development of tissues and organs, requires the ordered activation and silencing of thousands of genes in a spatially and temporally controlled manner. Many of these developmental processes are controlled by tissue-specific transcription factors. In addition, the maintenance of the differentiated state is often regulated by the same transcription factors required for formation of the mature cell. Mutations in 10 human (Table 290-1) transcription factor genes have been shown to disrupt mammalian eye development or maintenance. Mutations in an additional 18 mouse transcription factor genes have also been found to be associated with developmental abnormalities of the eye (Table 290-2). Human eye phenotypes (Table 290-1) can involve one or more ocular structures. Developmental anomalies that affect many parts of the eye are termed panocular defects, whereas other abnormalities may be restricted to the anterior segment, posterior segment, or the differentiation or maintenance of photoreceptors.
Panocular defects are broad phenotypes that arise by at least two different general mechanisms. The first, best illustrated by heterozygous mutations in the paired/homeobox gene PAX6, reflects the fact that the gene is expressed in and required for the normal development and/or maintenance of all regions of the developing eye: both neural and pigmented retina, iris, lens, and surface ectoderm (Fig. 290-2). Thus, PAX6 mutations cause panocular disease in the sense that many different parts of the eye may be affected, although in many patients only one region is predominantly abnormal. The second mechanism by which panocular defects arise reflects the fact that a gene expressed in one region of the developing eye may nevertheless be essential, via secondary physiological processes, for the normal development of other ocular structures. This mechanism is illustrated by the abnormalities that result from mutations in the CHX10 homeobox gene because, at least in the two patients identified to date, the eye is small and many structures are abnormal, even though the developmental expression of CHX10 in the eye is restricted solely to the progenitor cells of the neuroretina.
PAX6, mapping to chromosome 11p13, is a transcription factor with both a paired- and a homeodomain. It is mutated in aniridia and related anomalies. Most aniridia mutations lead to premature protein truncations, and haploinsufficiency. Cases classified as aniridia always have severe iris hypoplasia and usually one or more of the following features: foveal/macular hypoplasia, cataracts, glaucoma, and corneal limbal insufficiency, making this a panocular and progressive developmental disease. More infrequently (<10 percent of cases analyzed) missense mutations are seen. Foveal hypoplasia, Peters anomaly, corectopia and cataracts have been observed in these amino acid substitution cases. These “variant” phenotypes usually have less severe or no iris involvement. The universal involvement of PAX6 in the development of the eye in species ranging from Drosophila to humans serves as a paradigm for wide-ranging evolutionary conservation of key developmental regulators. This concept allows us to use a broad range of model organisms to understand gene function and define interacting developmental pathways. Although there is no reduction in eye size in aniridia, the heterozygous null mouse Small eye mutant is a good model for the ...