Pervasive mislocalization of pathogenic coding variants underlying human disorders

Area of Science:

• Human genetics
• Molecular biology
• Cell biology

Background:

• Thousands of disease-causing missense variants are identified through sequencing.
• Assessing the functional impact of these variants is a significant bottleneck in genetic research.

Approach:

• Developed a high-throughput imaging platform to assay the impact of coding variation on protein localization.
• Evaluated 3,547 missense variants across over 1,000 genes and associated phenotypes.

Key Points:

• Protein mislocalization is a common consequence of coding variation, affecting approximately one-sixth of pathogenic missense variants.
• Mislocalization impacts all cellular compartments and is observed in both recessive and dominant disorders.
• The primary drivers of mislocalization are effects on protein stability and membrane insertion.

Conclusions:

• Mislocalization patterns offer insights into pleiotropy, disease severity, and variants of unknown significance.
• This publicly available resource will accelerate the understanding of coding variation in human diseases.