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Widespread macromolecular interaction perturbations in human genetic disorders.

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.
Cell; 161(3): 647-660, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25910212
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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