Interpreting the molecular mechanisms of disease variants in human transmembrane proteins

Next-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. Here, we investigate missense variants in membrane proteins-key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. To accurately predict variant consequences, one fundamentally needs to understand the underlying molecular processes. A key mechanism underlying pathogenicity in missense variants of soluble pro-teins has been shown to be loss of stability. Membrane proteins, however, are widely understudied. Here, we interpret variant effects on a larger scale by performing structure-based estimations of changes in thermodynamic stability using a membrane -specific energy function and analyses of sequence conservation during evolution of 15 transmembrane proteins. We find evi-dence for loss of stability being the cause of pathogenicity in more than half of the pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mech-anistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.

Automated summary

Next-generation sequencing of human genomes has identified millions of missense variants, some of which may contribute to the development of diseases by causing loss of protein function. In this study, we focused on missense variants in membrane proteins, which play crucial roles in cell signaling and recognition. Our findings suggest that loss of stability is a driving factor in the pathogenicity of membrane protein variants, highlighting the importance of understanding the underlying molecular processes.