Genetic models of human disease

Notwithstanding that the 20-25,000 genes that humans have is fewer than was previously thought, the function is known for only a fraction of them. Whilst some experiments can be done on cells in culture, or on yeast or bacteria, a full understanding of the function of many genes can only come from studying them in the whole organism. Humans with genetic disease provide one way of studying the effect of the lack of a particular gene. As all mammals have virtually the same genetic content as humans, another approach is to study mice with genetic mutations.

We have identified mouse models of a number of human diseases, including genetic eye defects such as glaucoma, congenital diaphragm problems, neurological disease, kidney disease and stroke. Understanding how defective genes lead to disease not only helps understand those diseases that have a genetic component but also leads to the biological pathways that are affected in non-genetic disease, and may ultimately aid in the design of therapies for many.

The aim of this programme is to use mouse genetics and genomics to explore gene function, as it relates to human development, physiology and disease and to identify mouse models of human disease. We have previously discovered more than 25 new mutations that affect eye development and function, and, with the aid of the mouse genome sequence, have identified the affected gene in almost all of them. Most of the mutations result in lethality when homozygous and identify genes that are important in a range of biological processes. In addition, we have used deletions to reveal recessive mutations that localise to particular genomic locations.

We will continue characterisation of several of these mutant genes, two of which have known human disease homologues; Pax2, causing eye and kidney defects and Lmx1b causing nail-patella syndrome, and including glaucoma. This latter gene is subject to a collaboration with Simon John in the Jackson Labs, USA. A third mutant, for which we are still to confirm the affected gene, results in the congenital diagphragmatic hernia, a common human birth defect.

One of the mutations revealed in the deletion analysis results in hair loss, and is a mutation in a palmityl transferase protein, which results in loss of a palmitoylation activity. Palmitoylation is a dynamic process which regulates the association of a protein with the cell membrane. The key substrate of this enzyme is unknown, although we have some affected candidates. This is the subject of a collaborative project with Ian Smyth at Monash.

We have carried out a screen for novel recessive embryonic mutations, and identified a number of interesting genes which interact with the hedgehog signalling pathway.

We have extended our collaboration with MRC Mammalian Genetics Unit, Harwell to screen for recessive mutations that affect vision and eye development. We have at least 5 new confirmed recessive mutations affecting eye morphogenesis, and have identified the affected gene in three of them.

We are partners in the Eumodic programme, in which several hundred "knockout" mouse lines will be generated and comprehensively screened for defects in many systems of clinical importance. We will take any lines which demonstrate vision or other eye problems and extend the analysis to a more detailed histological level.