Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders

Abstract

SUMMARY 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.

A framework for exhaustively mapping functional missense variants

“…Beyond complementation, assays of protein interaction can, in addition to identifying variants directly impacting interaction, can detect variants ablating overall function through effects on protein folding or stability. In a recent study, approximately two‐thirds of disease‐causing variants were found to impact at least one protein interaction (Sahni et al , 2015). Although only a minority of human protein interactions have been mapped (Rolland et al , 2014), already 40% of human genes have at least one interaction partner detectable by yeast two‐hybrid assay in a recent screen (Rolland et al , 2014).…”

Variant Interpretation: Functional Assays to the Rescue

“…[39][40][41][42][43][44] Moreover, protein interactions can reveal defects in protein folding and stability, which helps to explain why approximately one-third of disease-related variants in proteins with multiple interaction partners disrupt all of the interactions of that protein. 45 Variants of protein-coding genes can also result in pathogenicity by altering splicing. 35% of all variants in disease-related genes have been suggested to directly affect splicing by modifying cis-regulatory elements.…”

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

“…48 Recently, network modeling has been introduced in order to explain how specific mutations may lead to distinct phenotypes. 44,46,[49][50][51] In a specific network model called the edgetic perturbation model, a mutation is considered to alter molecular interactions either due to edgetic perturbations or due to node removal ( Figure 4). Edgetic perturbation leads to the removal or addition of specific interactions while all other interactions (or edges) remain equal.…”