Grant: Project Grant

Cardiac arrhythmias are life-threatening conditions whereby the heart beats irregularly and blood flow to the brain can be temporarily restricted. This can lead to fainting or, in worse cases, to sudden death. Knowing which type of arrhythmia someone has is absolutely key to adjust the lifestyle appropriately and to receive the proper treatment. Many arrhythmias have a clear genetic cause, and typically certain genes are linked to very specific types of arrhythmia. We know that mutations in specific genes can lead to cardiac mutations, but in most cases we don't know how. We simply know that 'somehow a mutation in gene X or Y triggers this or that particular arrhythmia'. In this project, we wish to solve this problem, by investigating the direct mechanisms of individual mutations. In particular, we will investigate several mutations in a gene known as 'CALM'. These mutations have been found in various patients worldwide that have cardiac arrhythmias. Surprisingly, depending on the exact mutation within the CALM gene, the arrhythmia is different. We wish to pinpoint exactly how each mutation works, and how it affects the electrical properties of the heart. Almost every gene in our DNA forms a code to make protein. Ultimately, it is the protein, and not the gene, that plays the actual role in our bodies. A mutation in a gene thus leads to a slightly different protein, which could then result in differences large enough to cause a serious disorder. One problem is that proteins are so small that they are hard to visualize via regular microscopy. We therefore use a highly advanced technique, known as 'X-ray crystallography', whereby we can easily see differences smaller than a 10-billionth of a meter. Here we will compare normal and diseased forms of the protein encoded by the CALM gene. This will yield important insights into the exact mechanism of the disease.