Congenital heart diseases are the most common organ defects. They occur in about one percent of newborns. A large number of genes are involved in a heart dysfunction. For many congenital heart diseases, such as Noonan Syndrome, the link between the genetic changes (mutations) and the heart malformations have not yet been fully understood. The possibilities for treatment are limited. In most cases, they are limited to attenuate the symptoms of the disease.
Scientists at the Heart Center of the University Medical Center Göttingen (UMG) and the Cluster of Excellence “Multiscale Bioimaging” (MBExC) have for the first time been able to identify the link between the underlying gene mutations and the development of heart muscle thickening (heart hypertrophy) for the congenital heart disease Noonan Syndrome. According to their findings, mutations in one gene, the LZTR1 gene, are the cause of the development of symptoms in some previously unexplained clinical cases. The gene regulates essential signaling pathways for cell differentiation and growth. Modified variants of the gene are the starting point for a clinically transferable, personalized therapy option using "gene editing". The results were published in the renowned journal "Circulation".
Noonan syndrome is a genetic disease that is associated with developmental disorders. Typical symptoms include growth retardation and dwarfism, facial malfor-mations and serious heart defects. The genetic changes underlying the disease cause an overactivation of the so-called RAS-MAP kinase signaling pathway. This pathway is involved in many biological processes, e.g. cell differentiation and cell growth.
The interdisciplinary research was carried out under the project lead of Dr. Lukas Cyganek, head of the Stem Cell Unit at the UMG, and Prof. Dr. Bernd Wollnik, director of the Institute for Human Genetics at the UMG. Those involved included the Department of Cardiology and Pneumology (Director: Prof. Dr. Gerd Hasenfuß), the Department of Paediatric and Adolescent Medicine - Paediatric Cardiology, Intensive Care Medicine and Pneumology (Director: Prof. Dr. Thomas Paul) and the Institute of Pharmacology and Toxicology (Director: Prof. Dr. Wolfram-Hubertus Zimmermann) of the UMG. The research was funded by the German Research Foundation (DFG), the Collaborative Research Center 1002, the German Centre for Cardiovascular Research (DZHK), and by the Cluster of Excellence “Multiscale Bioimaging” (MBExC).
Original publication: Ulrich Hanses, Mandy Kleinsorge, Lennart Roos, Gökhan Yigit, Yun Li, Boris Barbarics, Ibrahim El-Battrawy, Huan Lan, Malte Tiburcy, Robin Hindmarsh, Christof Lenz, Gabriela Salinas, Sebastian Diecke, Christian Müller, Ibrahim Adham, Janine Altmüller, Peter Nürnberg, Thomas Paul, Wolfram-Hubertus Zimmermann, Gerd Hasenfuss, Bernd Wollnik, and Lukas Cyganek. Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy. Circulation. July 6th, 2020. doi:10.1161/CIRCULATIONAHA.119.044794
Scientific contacts: Dr. Lukas Cyganek, Stem Cell Unit, University Medical Center Göttingen, Georg-August University, lukas.cyganek(at)med.uni-goettingen.de
Prof. Dr. Bernd Wollnik, Institute for Human Genetics, University Medical Center Göttingen, Georg-August University, bernd.wollnik(at)med.uni-goettingen.de