Genetic architecture of retinoic-acid signaling-associated ocular developmental defects

Ocular developmental anomalies are among the most common causes of severe visual impairment in newborns (combined incidence 1-2:10,000). They comprise a wide range of inborn errors of eye development with a spectrum of overlapping phenotypes and they are frequently associated with extraocular malformations, neuropsychomotor developmental delay and/or intellectual disabilities. Many studies from model organisms have demonstrated the role of retinoic acid (RA) during organogenesis, including eye development, and have revealed the wide spectrum of malformations that can arise from defective RA signaling. However, genes coding for homeobox proteins and morphogenetic factors were implicated in anomalies of ocular development long before genes coding for RA-signaling proteins. The purpose of this review is to discuss current knowledge about the highly complex genetic architecture of RA-signaling-associated ocular developmental anomalies in humans. Despite less than a dozen genes identified thus far, all steps of RA-signaling, from vitamin A transport to target cells to transcriptional activation of RA targets, have been implicated. Furthermore, the majority of these genetic disorders are associated with both dominant and recessive inheritance patterns and a wide spectrum of ocular malformations, which can dominate the phenotype or represent one of many features. Although some genotype-phenotype correlations are described, in many cases, the variability of clinical expression cannot be accounted for by the genotype alone. This observation and the large number of unsolved cases suggest that the relationship between RA signaling and eye development deserves further investigation.