Article (Scientific journals)
Widespread macromolecular interaction perturbations in human genetic disorders.
Sahni, Nidhi; Yi, Song; Taipale, Mikko et al.
2015In Cell, 161 (3), p. 647-660
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Keywords :
DNA-Binding Proteins/genetics/metabolism; Disease/genetics; Genome-Wide Association Study; Humans; Mutation, Missense; Open Reading Frames; Protein Folding; Protein Interaction Maps; Protein Stability; Proteins/genetics/metabolism
Abstract :
[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Sahni, Nidhi
Yi, Song
Taipale, Mikko
Fuxman Bass, Juan I.
Coulombe-Huntington, Jasmin
Yang, Fan
Peng, Jian
Weile, Jochen
Karras, Georgios I.
Wang, Yang
Kovacs, Istvan 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
Barabasi, Albert-Laszlo
CHARLOTEAUX, Benoit ;  Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science (CEGS), Dana-Farber Cancer Institute, Boston, MA 02215, USA ; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Hill, David E.
Hao, Tong
Roth, Frederick P.
Xia, Yu
Walhout, Albertha J. M.
Lindquist, Susan
Vidal, Marc
More authors (38 more) Less
Language :
English
Title :
Widespread macromolecular interaction perturbations in human genetic disorders.
Publication date :
2015
Journal title :
Cell
ISSN :
0092-8674
eISSN :
1097-4172
Publisher :
Cell Press, United States - Massachusetts
Volume :
161
Issue :
3
Pages :
647-660
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2015 Elsevier Inc. All rights reserved.
Available on ORBi :
since 22 August 2019

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