Cardiomyopathy

Another of our areas of research focus is the study of familial forms of cardiomyopathy, which is a leading cause of sudden cardiac death amongst young and apparently healthy individuals. Cardiomyopathy is classified into four main forms, hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular dysplasia (cardiomyopathy). Mutations within a number of genes encoding the ‘sarcomeric' proteins, which form part of the contractile apparatus of the heart muscle, are well known as a common cause of this condition. As with the HSPs, we also study other forms of cardiomyopathy in order to learn as much as possible about the condition.

MYBPC3

As part of Windows of Hope we identified a form of hypertrophic cardiomyopathy affecting newborn children that is associated with very poor prognosis and death within the first year of life. Our studies of the DNA from these children revealed that mutations within the MYBPC3 gene cause this disease. Mutations in this gene were already known to be one of the most frequent genetic causes of adult forms of cardiomyopathy, but it was not recognised as a cause of severe childhood disease. In collaboration with Dr. Kenneth Zahka (Rainbow Children's, Cleveland) we are now undertaking an extensive project to investigate adult disease in the community.

Plakoglobin

As part of an international collaborative group we previously found the first gene for a form of cardiomyopathy termed ‘arrhythmogenic right ventricular cardiomyopathy’ (ARVC) which was also associated with a skin abnormality. The gene that we identified for this form of ARVC (plakoglobin) is a component of the 'desmosome', a key part of the adhesion machinery of heart cells, and these were the first findings to suggest that defective heart muscle integrity caused by defective cell-cell adhesion can cause ARVC. Subsequent studies by another group discovered that mutations in desmoplakin, another component of the desmosome, cause another form of ARVC.

Desmocollin 2

The above findings led us to look for further evidence of defective desmosome function in other forms of ARVC associated with skin disorder. We studied two siblings with ARVC associated with mild skin abnormality. Gene mapping studies in this family led to the positioning of the causative gene on chromosome 18. The desmocollin genes, also involved in desmosome-mediated cell adhesion, were located in the middle of the 'linked' region. Our sequence analysis of desmocollin 2 revealed a mutation in this family, which was the first reported case of autsomal recessive mutation of this gene associated with ARVC. 

We have also undertaken extensive studies of other conditions in which cardiomyopathy is often seen. These include studies of Noonan syndrome, an autosomal dominant disorder with multiple developmental defects associated with cardiovascular disease, as well as studies of animal forms of cardiomyopathy.  To see the publications from our laboratory on call of the above conditions involving cardiomyopathy, please click here.