The genetic and molecular basis of congenital eye defects

Key Points Mutations that lead to clinically relevant eye phenotypes (such as anophthalmia, microphthalmia, aniridia, coloboma and cataract) highlight important steps in the development of this organ. This information allows us to establish a genetic hierarchy in which genes such as PAX6 , SIX3 and SOX2 lie at the top, other genes (such as FOXC1 , FOXE3 , PITX3 and MAF ) function downstream and tissue-specific genes such as the crystallin-encoding genes are the final targets. The ongoing and rapidly increasing characterization of mutations in humans and mice indicates that the frequency of mutations that lead to eye defects is not randomly distributed among the genes that are involved in eye development: some genes (including PAX6 , PAX2 and CRYG ) are frequently affected by mutations, whereas others are not targeted either by spontaneous or experimentally induced mutations in the mouse. Allelic series of mutations show that similar clinical phenotypes might be caused by mutations in different genes; by contrast, mutations in the same gene do not necessarily lead to the same phenotype, which indicates the importance of as yet unknown modulators of gene expression or function. The detailed molecular analysis of allelic series of mutations will also allow detailed genotype–phenotype correlations to be made, which should uncover the function of particular domains of the mutated proteins. The mature eye is a complex organ that develops through a highly organized process during embryogenesis. Alterations in its genetic programming can lead to severe disorders that become apparent at birth or shortly afterwards; for example, one-half of the cases of blindness in children have a genetic cause. This review outlines the genetic basis of eye development, as determined by mutation analysis in patients and in model organisms. A better understanding of how this intricate organ develops at the genetic and cellular level is central to our understanding of the pathologies that afflict it.