June 25, 2015
A study published in Cell uses high-throughput functional assays for an extensive characterisation of the effects of disease-associated missense genetic variants, which result in amino acid substitutions in the encoded proteins. They categorised the mutations according to the extent to which they abolished protein–protein interactions (PPIs). They were classified as ‘quasi-null’ when they terminated all interactions, ‘edgetic’ when a subset of specific interactions were abolished, and ‘quasi-wild-type’ when none of interactions were apparently affected. They found that most of the disease-associated mutations that had functional consequences on PPIs and were either edgetic or quasi-null in contrast with the normal human variation, which were largely quasi-wild-type. Thus the authors believe that “this interaction profiling could be a useful tool to distinguish benign from disease-causal variants.”
The authors stated that “this functional analysis performed favourably compared with purely computational predictors of variant deleteriousness, and the number of PPIs disrupted by the mutations correlated positively with disease severity.” Overall, the authors believe that their study offers a worthwhile strategy to investigate the functional consequences of disease-associated genetic variants.