Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies
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- Daniel Reichart
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Eric L. Lindberg
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Henrike Maatz
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Antonio M. A. Miranda
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Anissa Viveiros
- Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
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- Nikolay Shvetsov
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Anna Gärtner
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany.
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- Emily R. Nadelmann
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Michael Lee
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Kazumasa Kanemaru
- Cellular Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
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- Jorge Ruiz-Orera
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Viktoria Strohmenger
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Daniel M. DeLaughter
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Giannino Patone
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Hao Zhang
- Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
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- Andrew Woehler
- Systems Biology Imaging Platform, Berlin Institute for Medical Systems Biology (BIMSB), Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), 10115 Berlin, Germany.
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- Christoph Lippert
- Digital Health-Machine Learning group, Hasso Plattner Institute for Digital Engineering, University of Potsdam, 14482 Potsdam, Germany.
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- Yuri Kim
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Eleonora Adami
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Joshua M. Gorham
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Sam N. Barnett
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Kemar Brown
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Rachel J. Buchan
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Rasheda A. Chowdhury
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Chrystalla Constantinou
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- James Cranley
- Cellular Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
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- Leanne E. Felkin
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Henrik Fox
- Heart and Diabetes Center NRW, Clinic for Thoracic and Cardiovascular Surgery, University Hospital of the Ruhr-University, 32545 Bad Oeynhausen, Germany.
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- Ahla Ghauri
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Jan Gummert
- Heart and Diabetes Center NRW, Clinic for Thoracic and Cardiovascular Surgery, University Hospital of the Ruhr-University, 32545 Bad Oeynhausen, Germany.
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- Masatoshi Kanda
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Ruoyan Li
- Cellular Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
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- Lukas Mach
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Barbara McDonough
- Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115, USA.
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- Sara Samari
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Farnoush Shahriaran
- Computational Health Center, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764 Neuherberg, Germany.
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- Clarence Yapp
- Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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- Caroline Stanasiuk
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany.
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- Pantazis I. Theotokis
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Fabian J. Theis
- Computational Health Center, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764 Neuherberg, Germany.
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- Antoon van den Bogaerdt
- ETB-Bislife Foundation, 2300 AH Leiden, Netherlands.
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- Hiroko Wakimoto
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- James S. Ware
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Catherine L. Worth
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Paul J. R. Barton
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Young-Ae Lee
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Sarah A. Teichmann
- Cellular Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
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- Hendrik Milting
- Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany.
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- Michela Noseda
- National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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- Gavin Y. Oudit
- Division of Cardiology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
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- Matthias Heinig
- Computational Health Center, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), 85764 Neuherberg, Germany.
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- Jonathan G. Seidman
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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- Norbert Hubner
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
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- Christine E. Seidman
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
説明
<jats:p>Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.</jats:p>
収録刊行物
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- Science
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Science 377 (6606), eabo1984-, 2022-08-05
American Association for the Advancement of Science (AAAS)
