The identification of the genetic factors, their function and the pathways in which they act are expected to contribute to a better understanding of the pathogenesis of the related diseases, ultimately leading to improved diagnosis, treatment and prevention. The elucidation of the pathways leading to the diseases promises the identification of novel drug targets for the benefit of a large patient population.
We identify mutations causing genetic diseases as a tool for finding novel candidate genes for drug therapy. We look at the pathways in the hopes that we will be able to manipulate the pathway to affect its function.
We are not limited to or focusing on a specific disease. I speak to physicians to determine promising diseases, in terms of there being sufficient genetic information for us to be able to work on. So we research topics as diverse as the cause of thyroid carcinoma, heart diseases (e.g. dilated cardiomyopathy, heart malformations), metabolic diseases, male infertility, etc.
We begin by looking at the clinical presentations in the family. If we see a family with a clinical presentation where we think we can identify the gene causing this, will proceed. This is dependent on the size of the family, the pattern of inheritance in the family, etc. Something caused by one gene in a large enough family with enough affected and unaffected members should provide enough information for us to find the gene. Bedouins have lots of genetic diseases – because of intermarriage, the recessive genes present more frequently.
We take from bioinformatics the pathway/function that is affected, to show that the mutation does affect function and play a role in the disease, together with experimental determination of protein function, from protein expression through to animal models, so we check protein stability, the location of the protein in the cell, the pathways, and its effect, such as onautophagy. We develop animal models since often we’ll narrow down the potential genes but still need to ask what happens to the animal when the gene is not functioning and how, if the mutated gene is expressed in many tissues, usually only one system (such as the heart) is affected. Once it has been identified and shown in an animal model we then try to connect this to a new pathway – something is disturbed so we want to understand what is disturbed and then try to contribute – we have shown that when cells from a patient looked wrong and we inserted the correct version of the genes, their cells repaired what was wrong.