Pervasive mislocalization of pathogenic coding variants underlying human disorders.

Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease-causing. This creates a new bottleneck: determining the functional impact of each variant - largely a painstaking, customized process undertaken one or a few genes or variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,547 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disruptions of trafficking signals or specific interactions. Furthermore, mislocalization patterns help explain pleiotropy and disease severity and provide insights on variants of unknown significance. Our publicly available resource will likely accelerate the understanding of coding variation in human diseases.

Importance of Autophagy in Mediating Cellular Responses to Iron Overload in Cardiomyocytes.

Both iron overload and deficiency can promote development of cardiomyopathy. Advances in our knowledge from recent research have indicated numerous potential cellular mechanisms. Regulation of myocardial autophagy by iron is of particular interest and will be reviewed here. Autophagy is already well established to play a significant role in regulating the development of heart failure. This review will focus on regulation of autophagy by iron, crosstalk between autophagy and other cellular process which have also already been implicated in heart failure (oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, ferroptosis) and the therapeutic potential of targeting these interactions.