Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.

Autor:	Busley AV; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Gutiérrez-Gutiérrez Ó; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany., Hammer E; DZHK (German Center for Cardiovascular Research), Greifswald, Germany; Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany., Koitka F; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Mirzaiebadizi A; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Steinegger M; School of Biological Sciences, Seoul National University, Seoul, South Korea., Pape C; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany; Institute of Computer Science, Georg-August University Göttingen, Göttingen, Germany., Böhmer L; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany., Schroeder H; NMR Signal Enhancement Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany., Kleinsorge M; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany., Engler M; Institute of Applied Physiology, University of Ulm, Ulm, Germany., Cirstea IC; Institute of Applied Physiology, University of Ulm, Ulm, Germany., Gremer L; Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich GmbH, Jülich, Germany., Willbold D; Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich GmbH, Jülich, Germany., Altmüller J; Cologne Center for Genomics, University of Cologne, Faculty of Medicine, and University Hospital Cologne, Cologne, Germany; Genomics Platform, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine-Berlin, Berlin, Germany., Marbach F; Institute of Human Genetics, University Hospital Cologne, Cologne, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Hasenfuss G; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Zimmermann WH; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany; Translational Neuroinflammation and Automated Microscopy, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Göttingen, Germany., Ahmadian MR; Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Wollnik B; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany., Cyganek L; Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany; Translational Neuroinflammation and Automated Microscopy, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Göttingen, Germany. Electronic address: lukas.cyganek@gwdg.de.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Jul 23; Vol. 43 (7), pp. 114448. Date of Electronic Publication: 2024 Jul 13.
DOI:	10.1016/j.celrep.2024.114448
Abstrakt:	Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1 L580P by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1 L580P -specific disease mechanism provoking cardiac hypertrophy. The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers. LZTR1 complex dysfunction results in the accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data show that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Uni- or biallelic genetic correction of the LZTR1 L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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