To leverage the possibilities of genome sequencing in disease diagnosis, we need accurate methods to assess the pathogenicity of mutations. Despite the rapid increase in human genome sequencing, about half of the variants found in each newly sequenced genome are novel, and their relevance for disease is unknown. We and others have shown that many pathogenic protein variants have reduced protein stability, often leading to proteasomal degradation, low protein levels, and thus a loss- of-function phenotype. Further, we have used in silico saturation mutagenesis and biophysical modelling to predict changes in protein stability and protein levels in the cell.<br/>Specifically, we have shown that disease-associated missense variants in several proteins lead to folding defects and degradation. Most of these unstable variants were correctly identified by our biophysical calculations, suggesting a clear link between thermodynamic and cellular protein stability. Statistical sequence analyses indicate that these variants are extremely rare in homologous proteins, pointing to a likely detrimental effect of these variants, and in general evolutionary conservation of protein stability. In contrast, benign variants were predicted to be stable and more common in the statistical sequence analysis. We have consistently observed that at least 50% of pathogenic variants are destabilised in proteins implicated in cancer risk syndromes, metabolic and neurodegenerative diseases, indicating that loss of stability and subsequent degradation is an important mechanism of pathogenicity across a broad range of proteins and diseases. Ongoing research into components of the protein quality control system as well as stabilising small molecule binders may reveal strategies to rescue destabilised but otherwise functional variants, and thus potentially treat or prevent disease.

Loss of protein stability is a key mechanism of pathogenicity

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.