Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases

We previously published about this research in a story titled “The Extremely Rare Disease BPTA Syndrome may Lead Scientists to Prevent the Development of Cancer” which can be found here. The study was originally published in the research journal Nature. You can read the full text of the study here. 

This research team was affiliated with the Charité – Universitätsmedizin Berlin, the Max Planck Institute for Molecular Genetics (MPIMG), and the University Hospital Schleswig-Holstein (UKSH)

What Happened?

Brachyphalangy,  polydactyly, and tibial aplasia/hypoplasia (BPTA) syndrome is an incredibly rare genetic condition; only a handful of cases of this disorder have ever been diagnosed. A team of researchers and scientists sought to understand what caused this rare syndrome. In the process of doing so, the team believes they may have discovered a mechanism that may be important for the origins of a wide range of hereditary diseases. 

In genetic disorders, genetic changes, typically mutations, are usually what causes the symptoms to appear. Unfortunately, in many cases, it isn’t really clear why these mutations cause disease because the changes that take place affect specific proteins with a 3D structure and function within the cell that isn’t understood.

To identify the cause of BPTA syndrome, the team looked at genetic data from five different patients and found one alteration affecting a protein called HMGB1 that they all shared. Normally, the protein structure has a negative charge in the final third, but in the BPTA patients, the charge was positive instead. This was caused by a frameshift mutation. This change means that the protein bears a strong resemblance to other proteins that are concentrated around the cell nucleolus. 

The nucleolus is a portion of the cell nucleus where the factories that produce proteins are themselves put together. This is a critical role for the cell. The mutated HMGB1 proteins are pulled towards the nucleolus because of the charge shift and clump together. This leads to the solidification of the organelle, which causes a breakdown in the cell’s function. The cells with this mutated protein were more likely to die. 

This fascinating discovery led the research team to pursue their study further, and they began looking at more DNA records to see if they could find similar cases. They found 66 proteins affected by 600 mutations that swapped the charge to positive. 101 of the mutations that they team found had previously been linked to either the development of cancer or other diseases, including neurodevelopmental disorders. The team selected 13 of these proteins and found that in 12 of them a similar attraction to the nucleolus was present. In around half of the cases, the function of the nucleolus was impacted.

The team concluded that they may have found a mechanism that could play a role in a variety of genetic disorders, and speculated that new therapies could potentially be developed from the research, including an approach that could help prevent the development of cancer.

About BPTA Syndrome

Brachyphalangy, polydactyly and tibial aplasia/hypoplasia (BPTA) syndrome is an ultra-rare disease that is poorly known. The cause of BPTA syndrome is genetic mutation impacting the HMGB1 gene. Symptoms of the disease include various malformations impacting the bones, nervous system, face, extremities, and other organ systems. With only a handful of identified cases, treatments for BPTA syndrome are symptomatic and supportive, with no known cure. 

Why Does it Matter?

By discovering a mechanism that appears to play a role in a significant number of genetic diseases, as well as the development of cancer, these researchers may have made a major breakthrough that could lead to new, more effective treatment approaches that could prevent cancer and see vast improvements in outcomes for certain genetic illnesses.

“The mechanism that causes this disease, which we discovered in BPTA syndrome, could be implicated in many other diseases and conditions as well. So, we’ve opened a door that could help to explain many other diseases. The real work starts now.” – Prof. Dr. Denise Horn, lead study author, Institute of Medical and Human Genetics, Charité

There is clearly much more research to be done in order to figure out how this mechanism could be targeted. Another avenue that must be explored is how this mechanism could play a role in cancer:

 “Tumors are attributable to genetic changes in the affected cells. This means we may be able to prevent cancer from developing in the future by intervening in the cell’s self-organization, which is mediated by disordered sections of proteins.” – Dr. Denes Hnisz, head of research, Max Planck Institute for Molecular Genetics, third lead author