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Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
Busley, Alexandra Viktoria; Gutiérrez-Gutiérrez, Óscar; Hammer, Elke; Koitka, Fabian; Mirzaiebadizi, Amin; Steinegger, Martin; Pape, Constantin; Böhmer, Linda; Schroeder, Henning; Kleinsorge, Mandy; Engler, Melanie; Cirstea, Ion Cristian; Gremer, Lothar; Willbold, Dieter; Altmüller, Janine; Marbach, Felix; Hasenfuss, Gerd; Zimmermann, Wolfram-Hubertus; Ahmadian, Mohammad Reza; Wollnik, Bernd; Cyganek, Lukas.
Afiliación
  • 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), Universi
  • 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), Universi
  • 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), Universi
  • 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 Göttin
  • 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, Göttinge
  • 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), Universi
Cell Rep ; 43(7): 114448, 2024 Jul 23.
Article en En | MEDLINE | ID: mdl-39003740
ABSTRACT
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 LZTR1L580P 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 LZTR1L580P-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 LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas ras / Miocitos Cardíacos / Células Madre Pluripotentes Inducidas / Síndrome de Noonan Límite: Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas ras / Miocitos Cardíacos / Células Madre Pluripotentes Inducidas / Síndrome de Noonan Límite: Humans Idioma: En Revista: Cell Rep Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos