Mutation Causes Heart Muscle Disorder - Researchers Detect Genetic Defect

7 January 2007

A mutation in a gene responsible for the adhesion of adjacent cells of the heart is the cause of a potentially lethal heart muscle disorder. The evidence has been provided by a team of researchers including Dr. Arnd Heuser of the Max Delbruck Centre of Molecular Medicine (MDC) Berlin-Buch, Germany, Dr. Eva R. Plovie of the Massachusetts General Hospital (MGH) in Boston, USA, and Professor Ludwig Thierfelder (MDC and Helios Klinikum Berlin/Charite) and Dr. Brenda Gerull (MDC).

The scientists searched selectively mutations in the gene Desmocollin-2 (DSC2) in a pool of 88 unrelated patients suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC) and discovered a mutation that causes this cardiomyopathy. By switching off the gene in zebrafish embryos, they demonstrated that DSC2 is essential for normal myocardial structure and function. Their work has now been published in the American Journal of Human Genetics.

Heart-muscle disorders (cardiomyopathies) are prevalent worldwide but their origins are widely unknown. During the course of the arrhythmogenic right ventricular cardiomyopathy (ARVC), fatty and connective tissue replacement takes place in the right ventricular myocardium. This leads to a dysfunction of the heart-muscle which can result in arrhythmia and cardiac insufficiency. The consequence is an increased risk of sudden cardiac death, even in young people.

The heart of an adult beats about seventy-times in a minute or around 100,000 times a day. It is, therefore, exposed to high mechanical strains. Desmosomes are mechanical structures that keep the cells bound together as if connected with push buttons so that they will not rip while beating.

In collaboration with researchers from the University Hospital of Munster, Dr. Heuser (MDC) and Dr. Plovie (MGH) searched for genetic defects in the desmosomes within a pool of 88 unrelated patients. They searched for a mutation in the gene that carries the information for the protein Desmocollin-2 (DSC2) which is part of the desmosome structure. Mutations of other desmosomal proteins have previously been detected for ARVC. Therefore, the Berlin- and Boston-based researchers assumed that mutations in DSC2 could result in ARVC, too.

Dr. Heuser and Dr. Plovie could now demonstrate that the mutation in DSC2 gene results in a reduced DSC2 protein which causes ARVC. Furthermore, the switch off of the DSC2 in zebrafish embryos showed that DSC2 is necessary for normal embryonic cardiac development. In an adult organism, a lack of DSC2 leads to disordered heart contraction and difficulties in the conduction system of the heart.

(Source: American Journal of Human Genetics : Massachusetts General Hospital and Max Delbruck Centre of Molecular Medicine : January 2007.)