Journal
CELL
Volume 161, Issue 3, Pages 647-660Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.04.013
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Funding
- NHGRI [P50HG004233, RC4HG006066, R01HG001715]
- NIGMS [GM082971]
- NSF [CCF-1219007]
- NSERC [RGPIN-2014-03892]
- Krembil Foundation
- Canada Excellence Research Chair
- Ontario Research Fund-Research Excellence Award
- Pew Latin American Fellowship
- EMBO Long-Term Fellowship
- Division of Computing and Communication Foundations
- Direct For Computer & Info Scie & Enginr [1219007] Funding Source: National Science Foundation
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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.
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