Genes, Environment and
Evolution in Eye Development
and Malformations: PAX6, SOX2, OTX2

 

Summary

We are interested in defining genes that are involved in the development and functioning of the human eye. One way to define key players in this process is to identify genes involved in ocular malformations. The first three genes discovered turn out to play multiple major roles in eye and brain development. Using multiple models, we have explored how mutations cause abnormalities and have begun to uncover how such multi-tasking genes are regulated by DNA regions that are highly conserved through evolution and often lie in flanking genomic regions some distance from the parts of the gene that encode the protein product...

 

 

We have defined many different PAX6 mutations PAX6 mutation database which lead to aniridia and related abnormalities and from our findings made deductions about gene function. Our work is aided by the use of model systems: the mouse mutant Small eye, published work in the fruitfly Drosophila and its eyeless mutants, and from the use of PAX6-expressing cultured cells. Most recently we have also identified a pax6b mutation in zebrafish.

 

Interestingly PAX6 expression is not confined to the eye, but is also found in the brain and olfactory system, during development and adulthood. In aniridia patients we have observed subtle abnormalities in the forebrain and a reduced ability to recognise odours. PAX6 is also expressed in the spinal cord and the pancreas. Many more facets of PAX6 function remain to be explored. However, going back to the patients with PAX6 mutations has also been very informative, revealing subtle brain anomalies on high resolution MRI and providing insight into a mild, and probably remediable hearing anomaly, due to interhemispheric transfer problems in the brain of some adults and children with aniridia. These anomalies are not apparent in the mouse model and work is in progress to compare PAX6 expression in human and mouse development.

 

PAX6 is part of a network of genes with a role in eye development. In collaboration with Professor David FitzPatrick’s group we have uncovered further eye disease genes: SOX2 and OTX2.

 

 

 

 

 

left: Aniridia - absence of the iris
right: Retina of patient with OTX2 mutation

 

These two genes are associated with anophthalmia (absence of eye), microphthalmia (small, abnormal eye) and coloboma (incorrectly developed eye ball) - all part of the AMC phenotypic spectrum, which can be unilateral or bilateral. So far all these eye disease genes have been identified through rare cases where chromosomal breakpoints have pointed the way to the genes. We are now looking at how our disease genes work and how they interact in networks. This may uncover new candidate genes which are still needed, as the three known genes only account for less than half of all AMC cases.

 

Mild phenotype in patient with PAX6 missense mutation.

 

 

 

 

 

 

Our work is currently focused on three key areas

1. Genetics of developmental eye malformations (this page)
2. How gene expression is regulated
3. How stress response pathways modulate the effect of mutations

• Key Publications
• Collaborations and Laboratory Members

 

A striking feature of some of the developmental eye abnormalities we study is that they do not show regular Mendelian inheritance patterns and affected individuals quite often only have one malformed eye. We have studied how such phenotypic variability may arise.

 

Purpose

We want to understand how genes required for early development are involved in causing eye abnormalities. Identifying disease-causing genes can lead to definition of gene networks and interactions which can be further explored using cell biology and model organisms. Analysis of specific mutational mechanisms provides insight into how genes fullfil their tightly regulated functions. Function can be perturbed through disruption of the genomic regions some distance from the main body of a gene. Using model organisms we aim to explore how large evolutionarily conserved genomic domains control the finely-tuned expression of fundamental developmental genes like PAX6, SOX2 and OTX2. Severity of disease phenotypes varies even within families with identical mutations – we are exploring how the stress-induced chaperone HSP90 is implicated in phenotype modulation and cellular surveillance.

 

Approach, Progress and Future Work

 

Eye disease genes identified in humans and function explored in model organisms

Eye development is controlled by a hierarchy of key genes, many of which have highly conserved counterparts involved in this process from insects to humans. Much of our work has focused on what has been described as a "master regulator of eye development", the gene PAX6. Our interest in this gene is driven by its role in the human developmental eye abnormality called aniridia (absence of the iris). The spectrum of abnormalities in this relatively rare disease is variable, but visual impairment is always present. We have made a lot of progress in defining the role of PAX6 in normal eye development and how this goes wrong when one copy of the gene is mutated, leading to a disease with an autosomal dominant pattern of inheritance.