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 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.

PACT inhibits the replication of SARS‐CoV‐2 through the blockage of GSK‐3β‐N‐nsp3 cascade

“…However, the presence of viral RNA converts the dimer into a more compact formation where dimerized NTD and dimerized CTD are stacked together 51 . Mutations in intrinsically disordered regions in the protein, such as HMGB1, 52 could alter its structure, resulting in different abilities in mediating phase separation and the formation of biomolecular condensates. SR domain between NTD and CTD was identified to be the intrinsically disordered region of N protein, assumably responsible for the structural conversion of N protein with or without viral RNA.…”

“…However, the presence of viral RNA converts the dimer into a more compact formation where dimerized NTD and dimerized CTD are stacked together. 51 Mutations in intrinsically disordered regions in the protein, such as HMGB1, 52 could alter its structure, resulting in different abilities in mediating…”

May the force be with you: Nuclear condensates function beyond transcription control

“…Supporting this hypothesis, recent studies highlighted the correlation between dysfunctions in biomolecular condensation and pathological conditions. [ 40,41 ]…”

“…Supporting this hypothesis, recent studies highlighted the correlation between dysfunctions in biomolecular condensation and pathological conditions. [40,41] The CPs caused by mutations affecting the organization of the transcriptional condensates include KS, Charge syndrome (CS), Rubinstein-Taybi syndrome (RT), and Cornelia de Lange syndrome (CdLS), while mutations affecting PcG condensates include Weaver syndrome (WS), Cohen-Gibson syndrome (COGIS), and Imagawa-Matsumoto syndrome (IMMAS) (Figure 2 and Table 1).…”

A tale of (disordered) tail

“…but can be associated with transcription regulation, intracellular signalling, protein aggregation, and cellular fitness 1 . In a recent paper, Mensah et al used a wide array of techniques to establish a link between aberrant phase separation of the protein HMGB1 and a rare genetic disease, brachyphalangy, polydactyly and tibial aplasia/hypoplasia syndrome (BPTAS) 2 . They identified de novo frameshift mutations in the HMGB1 gene, which changed the intrinsically disordered acidic tail of HMGB1 into an arginine-rich basic tail resulting in an aberrant partitioning of the protein into the nucleolus, perturbing rRNA biogenesis (Fig.…”