Widespread macromolecular interaction perturbations in human genetic disorders.

Cell
Authors
Keywords
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.

Year of Publication
2015
Journal
Cell
Volume
161
Issue
3
Pages
647-60
Date Published
2015 Apr 23
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2015.04.013
PubMed ID
25910212
PubMed Central ID
PMC4441215
Links
Grant list
RC4 HG006066 / HG / NHGRI NIH HHS / United States
P50HG004233 / HG / NHGRI NIH HHS / United States
R01 HG001715 / HG / NHGRI NIH HHS / United States
P50 HG004233 / HG / NHGRI NIH HHS / United States
R01HG001715 / HG / NHGRI NIH HHS / United States
GM082971 / GM / NIGMS NIH HHS / United States
Howard Hughes Medical Institute / United States
U41 HG001715 / HG / NHGRI NIH HHS / United States
RC4HG006066 / HG / NHGRI NIH HHS / United States