Widespread macromolecular interaction perturbations in human genetic disorders

Cell. 2015 Apr 23;161(3):647-660. doi: 10.1016/j.cell.2015.04.013.

Abstract

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Mutation, Missense*
  • Open Reading Frames
  • Protein Folding
  • Protein Interaction Maps*
  • Protein Stability
  • Proteins / genetics*
  • Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Proteins