Increased Aggregation Is More Frequently Associated to Human Disease-Associated Mutations Than to Neutral Polymorphisms

PLoS Comput Biol. 2015 Sep 4;11(9):e1004374. doi: 10.1371/journal.pcbi.1004374. eCollection 2015 Sep.


Protein aggregation is a hallmark of over 30 human pathologies. In these diseases, the aggregation of one or a few specific proteins is often toxic, leading to cellular degeneration and/or organ disruption in addition to the loss-of-function resulting from protein misfolding. Although the pathophysiological consequences of these diseases are overt, the molecular dysregulations leading to aggregate toxicity are still unclear and appear to be diverse and multifactorial. The molecular mechanisms of protein aggregation and therefore the biophysical parameters favoring protein aggregation are better understood. Here we perform an in silico survey of the impact of human sequence variation on the aggregation propensity of human proteins. We find that disease-associated variations are statistically significantly enriched in mutations that increase the aggregation potential of human proteins when compared to neutral sequence variations. These findings suggest that protein aggregation might have a broader impact on human disease than generally assumed and that beyond loss-of-function, the aggregation of mutant proteins involved in cancer, immune disorders or inflammation could potentially further contribute to disease by additional burden on cellular protein homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology
  • Databases, Factual
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Mutation / genetics*
  • Polymorphism, Genetic / genetics*
  • Protein Aggregation, Pathological / genetics*
  • Protein Stability

Grant support

This work was supported by a grant from the Interuniversity Attraction Poles (IAP Network 6/43) of the Belgian Federal Science Policy Office (BelSPo), the Hercules Foundation (AKUL005 HER/08/061). GDB was supported by an IWT fellowship and a PDMK grant from the University of Leuven. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.