Widespread macromolecular interaction perturbations in human genetic disorders
Fuxman Bass, Juan
Roth, Frederick P.
Walhout, Albertha J. M.
Document TypeJournal Article
MetadataShow full item record
AbstractHow 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.
SourceCell. 2015 Apr 23;161(3):647-60. doi: 10.1016/j.cell.2015.04.013. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/49938
Full author list omitted for brevity. For the full list of authors, see article.
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