Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

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 synd

SUBMITTER: Mensah MA 

PROVIDER: S-EPMC9931588 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature