Title

Widespread macromolecular interaction perturbations in human genetic disorders

UMMS Affiliation

Program in Systems Biology; Program in Molecular Medicine

Publication Date

4-23-2015

Document Type

Article

Disciplines

Genetics | Molecular Biology | Molecular Genetics | Structural Biology | Systems Biology

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.

DOI of Published Version

10.1016/j.cell.2015.04.013

Source

Cell. 2015 Apr 23;161(3):647-60. doi: 10.1016/j.cell.2015.04.013. Link to article on publisher's site

Journal/Book/Conference Title

Cell

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

25910212