Aberrant phase separation and nucleolar dysfunction in rare genetic diseases
Nature, vol. 614, pp. 564–571
Abstract
Abstract Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions 1–3 . Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus 4,5 . This suggests that mutations in disordered proteins may alter condensate properties and function 6–8 . Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.
Authors 40
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Humboldt-Universität zu Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Max Planck Institute for Molecular Genetics · Charité - Universitätsmedizin Berlin
Affiliation as printed
BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Max Planck Institute for Molecular Genetics
Affiliation as printed
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Max Planck Institute for Molecular Genetics
Affiliation as printed
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Max Planck Institute for Molecular Genetics
Affiliation as printed
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Christian-Albrechts-Universität zu Kiel · University Hospital Schleswig-Holstein · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · University of Lübeck
Affiliation as printed
Exploratory Diagnostic Sciences, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany
Exploratory Diagnostic Sciences, Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
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Humboldt-Universität zu Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Max Planck Institute for Molecular Genetics · Charité - Universitätsmedizin Berlin
Affiliation as printed
BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Affiliation as printed
Center for Genomics and Transcriptomics (CeGaT), Tübingen, Germany
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Affiliation as printed
Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
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Carl von Ossietzky Universität Oldenburg · University Hospital Schleswig-Holstein
Affiliation as printed
Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Kiel, Germany
Department of Medical Genetics, Carl von Ossietzky University, Oldenburg, Germany
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University Hospital Schleswig-Holstein
Affiliation as printed
Department of Obstetrics and Gynecology, University Hospital Schleswig-Holstein, Kiel, Germany
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Carl von Ossietzky Universität Oldenburg · University Hospital Schleswig-Holstein
Affiliation as printed
Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein, Kiel, Germany
Department of Medical Genetics, Carl von Ossietzky University, Oldenburg, Germany
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Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
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University Hospital Schleswig-Holstein
Affiliation as printed
Department of Pediatrics, Pediatric Endocrinology and Diabetes, University Hospital Schleswig-Holstein, Schleswig-Holstein, Germany
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Katholisches Kinderkrankenhaus Wilhelmstift
Affiliation as printed
Handchirurgie, Katholisches Kinderkrankenhaus Wilhelmstift, Hamburg, Germany
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University of Social Welfare and Rehabilitation Sciences
Affiliation as printed
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
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Max Planck Institute for Molecular Genetics
Affiliation as printed
RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Affiliation as printed
Department of Obstetrics and Gynaecology, Queen Mary Hospital, Pok Fu Lam, Hong Kong
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Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany
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Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Pediatric Neurology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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University Hospital Schleswig-Holstein
Affiliation as printed
Department of Pediatrics, University Hospital Center Schleswig-Holstein, Kiel, Germany
Department of Pediatrics, University Hospital Center Schleswig‐Holstein, Kiel, Germany
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University Hospital Schleswig-Holstein
Affiliation as printed
Department of Radiology and Neuroradiology, Pediatric Radiology, University Hospital Schleswig-Holstein, Kiel, Germany
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University of Social Welfare and Rehabilitation Sciences
Affiliation as printed
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
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Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Radboud University Medical Center
Affiliation as printed
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
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University of Freiburg · University Medical Center Freiburg
Affiliation as printed
Institute of Human Genetics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Affiliation as printed
Zentrum für Kinder-und Jugendmedizin, Helios Kliniken Schwerin, Schwerin, Germany
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University Hospital Magdeburg · Otto-von-Guericke-Universität Magdeburg
Affiliation as printed
Institute of Human Genetics, University Hospital, Otto-von-Guericke University, Magdeburg, Germany
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Institute for Research in Biomedicine · Barcelona Institute of Science and Technology
Affiliation as printed
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
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Max Planck Institute for Molecular Genetics
Affiliation as printed
Microscopy Core Facility, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Institució Catalana de Recerca i Estudis Avançats · Institute for Research in Biomedicine · Barcelona Institute of Science and Technology
Affiliation as printed
ICREA, Passeig Lluís Companys 23, Barcelona, Spain
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
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Max Planck Institute for Molecular Genetics
Affiliation as printed
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Humboldt-Universität zu Berlin · Berlin-Brandenburger Centrum für Regenerative Therapien · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Max Planck Institute for Molecular Genetics · Charité - Universitätsmedizin Berlin
Affiliation as printed
BCRT-Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany
BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany
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Christian-Albrechts-Universität zu Kiel · University Hospital Schleswig-Holstein · University of Lübeck
Affiliation as printed
Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany
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Malte Spielmann corresponding
Christian-Albrechts-Universität zu Kiel · University Hospital Schleswig-Holstein · German Centre for Cardiovascular Research · Max Planck Institute for Molecular Genetics · University of Lübeck
Affiliation as printed
DZHK (German Centre for Cardiovascular Research), partner site Hamburg, Lübeck, Kiel, Lübeck, Germany. Malte.Spielmann@uksh.de
Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany. Malte.Spielmann@uksh.de
RG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany. Malte.Spielmann@uksh.de
Institute of Human Genetics, University Hospitals Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Kiel, Germany
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Denise Horn corresponding
Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin
Affiliation as printed
Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Denise.Horn@charite.de
Institute of Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Denes Hnisz corresponding
Max Planck Institute for Molecular Genetics
Affiliation as printed
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany. hnisz@molgen.mpg.de
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
Cited by 168 stored of 168
Cited by patents worldwide 1 (Lens.org)
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