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Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

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Niskanen,  Henri       
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Magalhães,  Alexandre P.       
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Basu,  Shaon       
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kalscheuer,  Vera M.       
Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Buschow,  Rene       
Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kraushar,  Matthew L.       
High-Resolution Neurogenetics (Matthew Kraushar), Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos,  Stefan       
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Spielmann,  Malte
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hnisz,  Denes       
Precision Gene Control (Denes Hnisz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Nature_Mensah et al_2023.pdf
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Citation

Mensah, M. A., Niskanen, H., Magalhães, A. P., Basu, S., Kircher, M., Sczakiel, H. L., et al. (2023). Aberrant phase separation and nucleolar dysfunction in rare genetic diseases. Nature, 614, 564-571. doi:10.1038/s41586-022-05682-1.


Cite as: https://hdl.handle.net/21.11116/0000-000C-9EF0-3
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 functions1,2,3. 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 function6,7,8. 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.