Cell Reports (Jul 2024)
Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome
- Alexandra Viktoria Busley,
- Óscar Gutiérrez-Gutiérrez,
- Elke Hammer,
- Fabian Koitka,
- Amin Mirzaiebadizi,
- Martin Steinegger,
- Constantin Pape,
- Linda Böhmer,
- Henning Schroeder,
- Mandy Kleinsorge,
- Melanie Engler,
- Ion Cristian Cirstea,
- Lothar Gremer,
- Dieter Willbold,
- Janine Altmüller,
- Felix Marbach,
- Gerd Hasenfuss,
- Wolfram-Hubertus Zimmermann,
- Mohammad Reza Ahmadian,
- Bernd Wollnik,
- Lukas Cyganek
Affiliations
- Alexandra Viktoria Busley
- 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
- Óscar Gutiérrez-Gutiérrez
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany
- Elke Hammer
- DZHK (German Center for Cardiovascular Research), Greifswald, Germany; Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
- Fabian Koitka
- 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
- Amin Mirzaiebadizi
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Martin Steinegger
- School of Biological Sciences, Seoul National University, Seoul, South Korea
- Constantin Pape
- 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
- Linda Böhmer
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
- Henning Schroeder
- NMR Signal Enhancement Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Mandy Kleinsorge
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany
- Melanie Engler
- Institute of Applied Physiology, University of Ulm, Ulm, Germany
- Ion Cristian Cirstea
- Institute of Applied Physiology, University of Ulm, Ulm, Germany
- Lothar Gremer
- Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich GmbH, Jülich, Germany
- Dieter Willbold
- Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich GmbH, Jülich, Germany
- Janine Altmüller
- 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
- Felix Marbach
- Institute of Human Genetics, University Hospital Cologne, Cologne, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
- Gerd Hasenfuss
- 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
- Wolfram-Hubertus Zimmermann
- 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
- Mohammad Reza Ahmadian
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Bernd Wollnik
- 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
- Lukas Cyganek
- 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; Corresponding author
- Journal volume & issue
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Vol. 43,
no. 7
p. 114448
Abstract
Summary: 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.
