Widespread macromolecular interaction perturbations in human genetic disorders

• Published in: Cell Vol. 161; no. 3; pp. 647 - 660
• Main Authors: Sahni, Nidhi, Yi, Song, Taipale, Mikko, Fuxman Bass, Juan I, Coulombe-Huntington, Jasmin, Yang, Fan, Peng, Jian, Weile, Jochen, Karras, Georgios I, Wang, Yang, Kovács, István A, Kamburov, Atanas, Krykbaeva, Irina, Lam, Mandy H, Tucker, George, Khurana, Vikram, Sharma, Amitabh, Liu, Yang-Yu, Yachie, Nozomu, Zhong, Quan, Shen, Yun, Palagi, Alexandre, San-Miguel, Adriana, Fan, Changyu, Balcha, Dawit, Dricot, Amelie, Jordan, Daniel M, Walsh, Jennifer M, Shah, Akash A, Yang, Xinping, Stoyanova, Ani K, Leighton, Alex, Calderwood, Michael A, Jacob, Yves, Cusick, Michael E, Salehi-Ashtiani, Kourosh, Whitesell, Luke J, Sunyaev, Shamil, Berger, Bonnie, Barabási, Albert-László, Charloteaux, Benoit, Hill, David E, Hao, Tong, Roth, Frederick P, Xia, Yu, Walhout, Albertha J M, Lindquist, Susan, Vidal, Marc
• Format: Journal Article Web Resource
• Language: English
• Published: United States Cell Press 23-04-2015
• Subjects: Disease - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins/genetics/metabolism; Genetics & genetic processes; Genome-Wide Association Study; Génétique & processus génétiques; Humans; Life sciences; Mutation, Missense; Open Reading Frames; Protein Folding; Protein Interaction Maps; Protein Stability; Proteins - genetics; Proteins - metabolism; Proteins/genetics/metabolism; Sciences du vivant
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.04.013

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.