Unstable Proteins and Inherited Disease

A recently published Nature study has conducted a large-scale experimental analysis (known as “Human Domainome 1”) of over 500,000 human missense variants across more than 500 protein domains, providing valuable insights into genetic diseases caused by protein instability. Researchers employed cutting-edge DNA synthesis and cellular assays to examine how mutations affect protein abundance and stability, offering an unprecedented dataset for clinical and computational research.

Missense variants, which alter protein amino acid sequences, account for approximately one-third of human genetic disorders. The study revealed that 60 percent of pathogenic missense variants destabilize proteins, particularly in recessive diseases. By focusing on structurally diverse protein domains, the research highlighted the critical role of stability in genetic fitness and pathogenicity.

A key finding for ophthalmology was that protein instability can act as a main driver in inherited cataract formation, as well as contributing to a number of development and neurological diseases. The study also discusses the CRX homeodomain, mutations of which can cause inherited retinal dystrophies. By understanding how these mutations destabilize the protein or disrupt its DNA-binding function, future clinicians could be able to develop targeted therapies addressing the underlying molecular mechanisms involved with such diseases.

The Human Domainome 1 dataset also allowed the researchers to integrate stability data with protein language models, identifying functional sites critical to protein interactions and evolution. This integrative approach enhanced the predictive power of computational tools and offered a clearer understanding of the molecular mechanisms underlying many genetic diseases, the authors report.