Phase Separation as a Missing Mechanism for Interpretation of Disease Mutations.

Abstract

It is unclear how disease mutations impact intrinsically disordered protein regions (IDRs), which lack a stable folded structure. These mutations, while prevalent in disease, are frequently neglected or annotated as variants of unknown significance. Biomolecular phase separation, a physical process often mediated by IDRs, has increasingly appreciated roles in cellular organization and regulation. We find that autism spectrum disorder (ASD)- and cancer-associated proteins are enriched for predicted phase separation propensities, suggesting that IDR mutations disrupt phase separation in key cellular processes. More generally, we hypothesize that combinations of small-effect IDR mutations perturb phase separation, potentially contributing to "missing heritability" in complex disease susceptibility.

• Authors: Brian Tsang, Iva Pritišanac, Stephen W Scherer, Alan M Moses, Julie D Forman-Kay
• Journal: Cell (Cell) Vol. 183 Issue 7 Pg. 1742-1756 (12 23 2020) ISSN: 1097-4172 [Electronic] United States
• PMID: 33357399 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• Intrinsically Disordered Proteins
• Proteome

Topics

• Chromatin (metabolism)
• Disease (genetics)
• Humans
• Intrinsically Disordered Proteins (genetics)
• Models, Biological
• Mutation (genetics)
• Proteome (metabolism)