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However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions\n                    <jats:sup>1\u20133<\/jats:sup>\n                    . Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus\n                    <jats:sup>4,5<\/jats:sup>\n                    . This suggests that mutations\u00a0in disordered proteins may alter condensate properties and function\n                    <jats:sup>6\u20138<\/jats:sup>\n                    . 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\n                    <jats:italic>HMGB1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-022-05682-1","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T12:03:55Z","timestamp":1675857835000},"page":"564-571","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Aberrant phase separation and nucleolar dysfunction in rare genetic diseases"],"prefix":"10.1038","volume":"614","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8080-8779","authenticated-orcid":false,"given":"Martin A.","family":"Mensah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8361-5531","authenticated-orcid":false,"given":"Henri","family":"Niskanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4097-338X","authenticated-orcid":false,"given":"Alexandre P.","family":"Magalhaes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2648-4827","authenticated-orcid":false,"given":"Shaon","family":"Basu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9278-5471","authenticated-orcid":false,"given":"Martin","family":"Kircher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrike L.","family":"Sczakiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1685-6842","authenticated-orcid":false,"given":"Alisa M. 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