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UTICA, N.Y., June 8, 2019 / PRNewswire / – Researchers at the Masonic Medical Research Institute (MMRI), Weill Cornell Medicine and the Beth Israel Deaconess Medical Center (BIDMC) have identified the molecular mechanisms by which RAF1 mutations in patients with Noonan syndrome (NS ) cause hypertrophic cardiomyopathy (HCM), a dangerous thickening of the heart muscle that can lead to heart failure and death. Posted online this week in the journal of the American Heart Association circulation, the new findings reveal that downstream effectors could serve as therapeutic targets for the treatment of HC badociated with SN.
Noonan syndrome is a disorder that involves unusual facial features, small size and a multitude of cardiac malformations, including pulmonary stenosis and atrioventricular septal malformations (AVSD). It is caused by mutations in one of the genes, including PTPN11, SOS1, RAF1 and KRAS, each of them modulates the function of the canonical pathway of protein-activated protein kinase RAS-Mitogen (MAPK), an important protein signaling cascade for the regulation of cell growth, differentiation and death. RAF1-badociated NS patients, often infants and young children, typically have a more devastating heart condition, a serious form of life-threatening CMH.
NS is the most common group of a group of rare conbad diseases called RASopathies, which include Costello syndrome, NS with multiple lentigines syndrome (formerly LEOPARD), neurofibromatosis, cardio-cutaneous-cutaneous syndrome, and others, and has a prevalence of about 1: 1000 to 1. 2500 children born each year worldwide.The mutations of RAF1 badociated with NS are even rarer, but the effects of this mutation are also much more serious than the other mutations supposed to be the cause of NS, "explained the main author. Maria Kontaridis, Ph.D., Director of Research at the Masonic Institute of Medical Research and Associate Professor of Medicine at the Beth Israel Deaconess Medical Center and Harvard Medical School.
"There is currently no treatment to prevent the onset of NS and protect against cardiac abnormalities badociated with RAF1 mutations at the origin of this disease," said the first author Fabrice Jaffré, PhD, biology instructor of the development and surgical biology at Weill Cornell. Drug. "Our studies have sought to model and understand the molecular mechanisms that trigger the disease and its cardiac characteristics so that we can identify new targeted treatments."
In the article, the investigators used RAF1 derived from the patientS257L / + and cardiomyocytes (iCM) derived from pluripotent stem cells (iPSC) induced by isogen control generated by CRISPR-Cas9 to model the HCM badociated with NS RAF1 and further delineate the underlying molecular mechanisms of the disease.
"The cardiomyocytes derived from the iPSC, badociated with genome editing technology such as CRISPR, can be a powerful system for modeling heart disorders such as HCM badociated with NS, so to decipher the underlying molecular mechanisms of the disease and, ultimately, to discover new therapeutic targets, "said Dr. Jaffré.
"Here, the results show that two parallel signaling pathways are involved in the development of HCM badociated with RAF1," Dr. Kontaridis said. "Specifically, the ERK5 signaling pathway works to increase the size of the cell, ie, hypertrophy, while the MEK1 / 2 signaling pathway is involved in regulating the function of the cell. cardiac sarcomere Both are needed to cause the HCM phenotype. "
"Together, these data indicate that this disease is not linear, there are multiple parallel signaling pathways that play an important role in determining the phenotype of the disease." One path may be needed, but not enough to it alone to cause this disorder; the use of potential combinatorial therapy for each of the pathways identified in this paper could lead to a promising approach in treating RAF1 patients badociated with SN with HCM, "said Dr. Kontaridis.
"Rare diseases have always been a window into the understanding of more common disorders," said Dr. Kontaridis. "By studying rare diseases and identifying the mechanisms behind these diseases, we will also be able to reveal potential therapeutic options for other more common diseases."
Additional study coauthors include Clint L. Miller, Center for Genomics for Public Health, Department of Public Health Sciences, Biochemistry and Molecular Genetics and Biomedical Engineering, University of Virginia; Anne Schänzer, Institute of Neuropathology, Giessen University Hospital, Justus Liebig University Giessen, Germany; Todd EvansDepartment of Surgery, Weill Cornell Medicine; Amy E. Roberts, Department of Cardiology, Division of Genetics, Boston Children's Hospital; and Andreas Hahn, Department of Child Neurology, Giessen University Hospital, Justus-Liebig University, Giessen, Germany.
This work was funded by the National Institutes of Health (grants R01-HL114775, R01-728 HL122238, R01-HL102368), the Harvard Stem Cell Research Institute (HSCI), the Saving Tiny Hearts Foundation and the Beth Israel Deaconess Medical Center. Department of Medicine, Division of Cardiology MIK; National Pathutes Grant 730 Pathway to Independence Institutes of Health (R00 HL12592) to C.L.M; the National Institutes of Health (R35-732 HLHL135778) and the Department of Defense (W81XWH-17-1-0661) in T.E .; and American Heart Association Scientific Development Grant (SDG # 16SDG30580000) and the Canadian Rare Disease Foundation to F.J.
About the Masonic Institute of Medical Research
The Masonic Medical Research Institute is an internationally recognized biomedical research institute founded by the Grand Lodge of Free and Accepted Masons in the State of New York in 1958. The goal of the Institute for Growth, Success and the Future is to establish a comprehensive cardiovascular research enterprise focused on the following areas: heart disease development, hypertrophy and heart failure, diabetes and metabolism , cardiac immunology and electrophysiology. We will also acquire and develop excellence in innovative technologies, such as pluripotent stem cells, genetics, signal transduction, in vivo animal model systems and the development of platforms for administration. of drugs to be used for the treatment of diseases. For more information, visit: www.mmri.edu
Contact: Joshua Poupore, 518-330-2250, [email protected]
SOURCE Masonic Institute of Medical Research
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