Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes, Shaon Basu, Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D. Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L. Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann (), Denise Horn () and Denes Hnisz ()
Additional contact information
Martin A. Mensah: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Henri Niskanen: Max Planck Institute for Molecular Genetics
Alexandre P. Magalhaes: Max Planck Institute for Molecular Genetics
Shaon Basu: Max Planck Institute for Molecular Genetics
Martin Kircher: Berlin Institute of Health at Charité–Universitätsmedizin Berlin
Henrike L. Sczakiel: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Alisa M. V. Reiter: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Jonas Elsner: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Peter Meinecke: University Medical Center Hamburg-Eppendorf
Saskia Biskup: Center for Genomics and Transcriptomics (CeGaT)
Brian H. Y. Chung: The University of Hong Kong
Gregor Dombrowsky: University Hospital Schleswig-Holstein
Christel Eckmann-Scholz: University Hospital Schleswig-Holstein
Marc Phillip Hitz: University Hospital Schleswig-Holstein
Alexander Hoischen: Radboud University Medical Center
Paul-Martin Holterhus: University Hospital Schleswig-Holstein
Wiebke Hülsemann: Handchirurgie, Katholisches Kinderkrankenhaus Wilhelmstift
Kimia Kahrizi: University of Social Welfare and Rehabilitation Sciences
Vera M. Kalscheuer: Max Planck Institute for Molecular Genetics
Anita Kan: Queen Mary Hospital
Mandy Krumbiegel: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Ingo Kurth: RWTH Aachen University Hospital
Jonas Leubner: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Ann Carolin Longardt: University Hospital Center Schleswig‐Holstein
Jörg D. Moritz: University Hospital Schleswig-Holstein
Hossein Najmabadi: University of Social Welfare and Rehabilitation Sciences
Karolina Skipalova: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Lot Snijders Blok: Radboud University Medical Center
Andreas Tzschach: University of Freiburg, Faculty of Medicine, University of Freiburg
Eberhard Wiedersberg: Helios Kliniken Schwerin
Martin Zenker: University Hospital, Otto-von-Guericke University
Carla Garcia-Cabau: The Barcelona Institute of Science and Technology
René Buschow: Max Planck Institute for Molecular Genetics
Xavier Salvatella: The Barcelona Institute of Science and Technology
Matthew L. Kraushar: Max Planck Institute for Molecular Genetics
Stefan Mundlos: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Almuth Caliebe: University of Lübeck and Kiel University
Malte Spielmann: Max Planck Institute for Molecular Genetics
Denise Horn: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Denes Hnisz: Max Planck Institute for Molecular Genetics

Nature, 2023, vol. 614, issue 7948, 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 functions1–3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6–8. 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.

Date: 2023
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DOI: 10.1038/s41586-022-05682-1

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