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. Copyright \copyright 2015 Elsevier Inc. All rights reserved.
%0 Journal Article
%1 Sahni2015Widespread
%A Sahni, Nidhi
%A Yi, Song
%A Taipale, Mikko
%A Fuxman Bass, Juan I.
%A Coulombe-Huntington, Jasmin
%A Yang, Fan
%A Peng, Jian
%A Weile, Jochen
%A Karras, Georgios I.
%A Wang, Yang
%A Kovács, István A.
%A Kamburov, Atanas
%A Krykbaeva, Irina
%A Lam, Mandy H.
%A Tucker, George
%A Khurana, Vikram
%A Sharma, Amitabh
%A Liu, Yang-Yu Y.
%A Yachie, Nozomu
%A Zhong, Quan
%A Shen, Yun
%A Palagi, Alexandre
%A San-Miguel, Adriana
%A Fan, Changyu
%A Balcha, Dawit
%A Dricot, Amelie
%A Jordan, Daniel M.
%A Walsh, Jennifer M.
%A Shah, Akash A.
%A Yang, Xinping
%A Stoyanova, Ani K.
%A Leighton, Alex
%A Calderwood, Michael A.
%A Jacob, Yves
%A Cusick, Michael E.
%A Salehi-Ashtiani, Kourosh
%A Whitesell, Luke J.
%A Sunyaev, Shamil
%A Berger, Bonnie
%A Barabási, Albert-László L.
%A Charloteaux, Benoit
%A Hill, David E.
%A Hao, Tong
%A Roth, Frederick P.
%A Xia, Yu
%A Walhout, Albertha J.
%A Lindquist, Susan
%A Vidal, Marc
%D 2015
%J Cell
%K ibse
%N 3
%P 647--660
%T Widespread macromolecular interaction perturbations in human genetic disorders.
%U http://view.ncbi.nlm.nih.gov/pubmed/25910212
%V 161
%X 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. Copyright \copyright 2015 Elsevier Inc. All rights reserved.
@article{Sahni2015Widespread,
abstract = {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. Copyright {\copyright} 2015 Elsevier Inc. All rights reserved.},
added-at = {2018-12-02T16:09:07.000+0100},
author = {Sahni, Nidhi and Yi, Song and Taipale, Mikko and Fuxman Bass, Juan I. and Coulombe-Huntington, Jasmin and Yang, Fan and Peng, Jian and Weile, Jochen and Karras, Georgios I. and Wang, Yang and Kov\'{a}cs, Istv\'{a}n A. and Kamburov, Atanas and Krykbaeva, Irina and Lam, Mandy H. and Tucker, George and Khurana, Vikram and Sharma, Amitabh and Liu, Yang-Yu Y. and Yachie, Nozomu and Zhong, Quan and Shen, Yun and Palagi, Alexandre and San-Miguel, Adriana and Fan, Changyu and Balcha, Dawit and Dricot, Amelie and Jordan, Daniel M. and Walsh, Jennifer M. and Shah, Akash A. and Yang, Xinping and Stoyanova, Ani K. and Leighton, Alex and Calderwood, Michael A. and Jacob, Yves and Cusick, Michael E. and Salehi-Ashtiani, Kourosh and Whitesell, Luke J. and Sunyaev, Shamil and Berger, Bonnie and Barab\'{a}si, Albert-L\'{a}szl\'{o} L. and Charloteaux, Benoit and Hill, David E. and Hao, Tong and Roth, Frederick P. and Xia, Yu and Walhout, Albertha J. and Lindquist, Susan and Vidal, Marc},
biburl = {https://www.bibsonomy.org/bibtex/233b56ef61983596438668260fafd84c0/karthikraman},
citeulike-article-id = {13592777},
citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/25910212},
citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=25910212},
day = 23,
interhash = {d493aebc6382055273a2318e3ebeefad},
intrahash = {33b56ef61983596438668260fafd84c0},
issn = {1097-4172},
journal = {Cell},
keywords = {ibse},
month = apr,
number = 3,
pages = {647--660},
pmid = {25910212},
posted-at = {2015-05-29 10:55:22},
priority = {2},
timestamp = {2018-12-02T16:09:07.000+0100},
title = {Widespread macromolecular interaction perturbations in human genetic disorders.},
url = {http://view.ncbi.nlm.nih.gov/pubmed/25910212},
volume = 161,
year = 2015
}