Branchio-oculo-facial syndrome is a severely debilitating congenital condition in which affected individuals exhibit various symptoms including cleft lip, malformed ears and nose, mental retardation and eye defects. It is an autosomal dominant condition which means that only one of the two copies of the gene that a person inherits (one from mother and one from father) needs to be faulty for the symptoms to be manifest. It was recently shown that the faulty gene causing the condition is TFAP2 - this gene encodes a transcription factor protein. Transcription factors are genetic switches that turn on or turn off the activity of many other genes - because of this, when transcription factors don't function, there can be many consequences for the developing embryo.
In this study, we aimed to find out if mutations in the TFAP2 gene might contribute to a wider range of eye defects than previously suspected. Our contribution to the project was to study the function of the gene in zebrafish. Working in parallel, our collaborators examined the TFAP2 gene in a cohort of patients and found mutations associated with various eye problems from anopthalmia (where the eye is missing) to coloboma (where there is a slit in one part of the eye). We showed that zebrafish with reduced function of the fish version of TFAP2 exhibited similar defects such as coloboma and cranio-facial deficits.
Of course, the development of a structure as complex as the eye requires the action of many genes working together and the next step in our project was to determine the consequences to eye development if more than one gene is defective. This is difficult to determine in humans but is simple in fish as there are techniques that allow us to simultaneously disrupt the function of two or more genes. We chose to examine the interactions between Tfap2 and genes encoding proteins functioning in two signaling pathways important for eye development. These signaling pathways are termed the Wnt and Bmp pathways and work from ourselves and others had already implicated these signals in the communication between cells that ensures normal eye formation.
Our most novel finding was that if Tfap2 function is just slightly compromised, there is no consequence on eye development if other genes are functioning properly (FIG 2A). However, if two genes are simultaneously disrupted, then the consequences can be devastating. We showed that if Tfap2 is partially non-functional in embryos with slightly increased Wnt signaling, then embryos exhibited anopthalmia (Figure 2B). If Tfap2 function is reduced alongside a reduction in Bmp signaling, then eyes exhibit coloboma (Figure 2C). These studies tell us that a mutation that could be "hidden" in absence of other genetic defects can predispose embryos to the deleterious consequences of mutations in other, interacting genes. Information of this type can be very helpful in determining genetic predisposition (risk) to eye problems that individuals or their children face.
There are many very large-scale studies in humans ongoing at the moment looking at genetic signatures for huge numbers of genes in huge numbers of individuals - the hope is that these studies will show correlations between genetic differences and disease manifestation. Studies in fish and other model systems will enable scientists to move beyond correlation and directly assess the function of genes implicated in these screening projects.
This study was a collaboration with Nicky Ragge and others and our work received financial support from