The implications of phase separation

It is very hard to understand the effects of disease mutations that are prevalent in intrinsically disordered protein regions (IDRs). In a Perspective published in the December 23, 2020 issue of Cell, a collaborative Toronto team from the groups of Julie Forman-Kay, Alan Moses and Steve Scherer put forward both general and specific hypotheses for how IDR mutations lead to pathology in complex diseases, particularly in autism spectrum disorder (ASD) and cancer.

A recently defined role of IDRs is in mediating phase separation in biomolecular condensates, which are increasingly understood to regulate key aspects of biological function. In this Perspective, the authors use bioinformatic analyses to show that ASD- and cancer-associated proteins are enriched for predicted phase separation via their IDRs. They describe how IDR mutations can perturb phase separation and specifically how disease-associated IDR mutations may dysregulate condensates involved in chromatin structure, transcription, splicing, translation, receptor activation and signaling, as well as synapse organization in neurons, leading to pathology. These ideas enable the intriguing suggestion that synergistic effects of mutations having small effects on phase separation within multi-component condensates may explain part of the missing heritability in complex diseases such as ASD and cancer.