Scientists at the Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine, Berlin-Buch, in cooperation with colleagues from Kiel, Boston, Zurich and London, have identified a gene responsible for the development of a congenital form of heart failure. In their study, they show that changes in the PRDM16 gene on chromosome 1 lead to heart failure. Further studies in zebrafish point to the fact that PRDM16 plays a role in embryonic heart development. The study by the interdisciplinary research team has been published in one of the leading journals in the field of genetics, the American Journal of Human Genetics*.
Congenital heart defects occur in 8 of every 1,000 newborn children and therefore represent one of the most common developmental disorders. The causes can usually be traced back to disturbances during the first three months of embryonic development. Many of these cases have been linked to a defect in the number or structure of human chromosomes. One of the most common chromosomal abnormalities in humans involves the loss of a particular region of chromosome 1, known as the 1p36 deletion syndrome. The loss of this region leads to a number of malfunctions in various organs. For example, the structure of the wall of the left ventricle of the heart develops abnormally, leading to early heart failure (cardiomyopathy).
A precise mapping of the genetic information lost on chromosome 1 carried out by the researchers revealed that only parts of a single gene, the PRDM16 gene, are lost in patients with this special heart abnormality. “Following our localization of the genomic locus, we also examined patients with the isolated form of this congenital cardiomyopathy for deviations in PRDM16, and were able to identify changes that impair the functioning of PRDM16,” says PD Dr. Sabine Klaassen, Physician and Researcher in the Charité Department of Pediatrics, Division of Cardiology and the Experimental and Clinical Research Center (ECRC). The team also demonstrated genetic changes in PRDM16 in 5 of 131 individuals with a pathological enlargement of the left heart, known as dilated cardiomyopathy, but in none of of the 6,400 persons examined as controls.
Next, using functional experiments in zebrafish, a model organism used in heart research, the researchers showed that PRDM16 plays a role in embryonic heart development. “The zebrafish model enables us to understand the function of the normal and the altered PRDM16 in the development of the heart,” explains Dr. Anne-Karin Arndt, Assistant Physician at the Clinic for Congenital Heart Defects and Pediatric Cardiology at the Schleswig-Holstein University Clinic in Kiel and first author of the publication. “Our successful identification of the functional effects of the gene defect in animal models should allow us, during the next phase, to develop therapies based on the understanding of the newly identified genetic changes.”
*Original publication: Arndt et al., Fine Mapping of the 1p36 Deletion Syndrome Identifies Mutation of PRDM16 as a Cause of Cardiomyopathy, The American Journal of Human Genetics (2013), http://dx.doi.org/10.1016/j.ajhg.2013.05.015
Privatdozentin Dr. Sabine Klaassen
PD Dr. Sabine Klaassen
Clinic for Pediatrics, Division of Pediatric Cardiology
Experimental and Clinical Research Center (ECRC)
Charité – Universitätsmedizin Berlin
Tel.: +49 30 450 540656 and +49 30 9406 3319
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