2026-04-03T19:38:25Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2002832025-11-19T19:20:40Zcom_2072_1057col_2072_478908col_2072_478917

00925njm 22002777a 4500 dc Mensah, Martin A. author Niskanen, Henri author Magalhaes, Alexandre P. author Basu, Shaon author Kircher, Martin author Sczakiel, Henrike L. author Reiter, Alisa M. V. author Elsner, Jonas author Meinecke, Peter author Biskup, Saskia author Chung, Brian H. Y. author Dombrowsky, Gregor author Eckmann-Scholz, Christel author Hitz, Marc Phillip author Hoischen, Alexander author Holterhus, Paul-Martin author Hülsemann, Wiebke author Kahrizi, Kimia author Kalscheuer, Vera M. author Kan, Anita author Krumbiegel, Mandy author Kurth, Ingo author Leubner, Jonas author Longardt, Ann Carolin author Moritz, Jörg D. author Najmabadi, Hossein author Skipalova, Karolina author Snijders Blok, Lot author Tzschach, Andreas author Wiedersberg, Eberhard author Zenker, Martin author Garcia Cabau, Carla author Buschow, René author Salvatella i Giralt, Xavier author Kraushar, Matthew L. author Mundlos, Stefan author Caliebe, Almuth author Spielmann, Malte author Horn, Denise author Hnisz, Denes author 2023-07-04T10:57:18Z 2023-07-04T10:57:18Z 2023-02-08 2023-06-30T13:12:19Z 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.© 2023. The Author(s). Genètica Proteïnes Genetics Proteins Aberrant phase separation and nucleolar dysfunction in rare genetic diseases