First-of-its-kind database reveals how DNA mutations 'destabilize' proteins, triggering genetic diseases

Scientists have created a mega-database revealing how half a million different DNA mutations generate errors in proteins in humans. Researchers hope the database will be used to develop new personalized drugs that directly reverse the effects of mutations.

The human genome contains instructions for at least 20,000 proteinswhich are essential for almost all physiological processes. Each building block of a protein – called an amino acid – is key to its function, and therefore the exchange of amino acids can essentially break a protein apart. “Missense” mutations—changes in a DNA sequence that exchanges one amino acid for another – in nearly 5,000 human proteins are known to cause genetic diseases, such as Huntington’s disease And cystic fibrosis.

However, in many cases it is unclear how these mutations affect protein structure and function and thus cause disease. Without this understanding, it is difficult to develop targeted treatments for genetic disorders without altering the genome itself, according to the authors of a new study published January 8 in the journal Nature.

“Depending on what happens to the protein, if you were to design a drug to try to cure the disease, then the approach would be completely different depending on the individual mutation you’re looking at,” Antoni Beltranlead author of the study and postdoctoral researcher at the Center for Genomic Regulation in Spain, told Live Science.

To address this problem, Beltran and his colleagues created a massive database that catalogs the effect of more than 500,000 missense mutations on the stability of 522 protein “domains”—that is, the regions of proteins that are essential for their function. They call the database a human “domainome,” and they built it by systematically triggering mutations in proteins in the lab. They then transferred the mutants into yeast cells and monitored the effects.

In the new study, the team focused in particular on 621 missense mutations in the database already known to cause disease in humans. They found that 60% of these mutations made the affected proteins less stable. Unstable proteins are more likely to misfold or distort; like origami, proteins must be folded in a particular way to achieve their intended shape. Misfolded proteins can accumulate in cells, potentially causing damage, or simply to be degraded by the body, leaving cells unable to function.

Image of a scientist using a pipette with a microtiter plate and a petri dish on a transparent table. The perspective of the image is as if looking at the scientist from the table.

The team that created the database hopes it will one day be used to develop personalized treatments for genetic diseases. (Image credit: nicolas_ via Getty Images)

For example, the hereditary form of cataract, an eye disease that obscures the lens. eye — is triggered by mutations in the genes of beta-crystallin proteins, which normally maintain the transparency of the lens. In the new study, Beltran and his colleagues found that 72% of these mutations destabilize crystal proteins, increasing the chance that they will clump together and form cloudy areas in the lens.

Rather than causing instability, some missense mutations caused different changes in the proteins. For example, some of the mutations causing Rett syndromea rare neurodevelopmental disorder, prevents a specific protein of DNA binding. This process would normally allow the protein to turn genes on and off in the brainbut in the syndrome it goes wrong.

Although it is the first and largest database of its kind, it only covers 2.5% of known human proteins so far. Additional work is therefore needed to widen it, Beltran acknowledged. Further research will also be needed to determine whether the effects observed in isolated domains also manifest in full-size proteins.

The team’s ultimate goal is to create a useful database for predicting the effect of any mutation on protein stability, Beltran said. Such a tool could theoretically allow scientists to develop better drugs against genetic diseases, targeting defects in the proteins that cause these diseases.