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This Could Be The Cause Of Many More Unresolved Diseases – And Now We ‘Know How To Look For It’

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According to an international team of researchers from clinical medicine and basic biology, proteins often occupy specific protein-dense droplets within cells known as “cellular condensates.” These proteins have sequence characteristics that serve as identifying markers, directing the protein to its proper condensate.

However, if these labels are disrupted, the proteins may end up in the incorrect condensate. The researchers believe that this misplacement could be the source of numerous unresolved illnesses.

The study’s results have been published in the prestigious journal Nature.

Individuals suffering from BPTA syndrome possess abnormal limbs, including shortened fingers and extra toes, along with missing tibia bones in their legs and reduced brain size.

The researchers discovered that the syndrome is brought on by a specific genetic alteration that leads to the migration of a critical protein to the nucleolus, a massive protein-rich droplet located in the cell nucleus. This disruption inhibits the function of the nucleolar condensate, leading to the manifestation of developmental disorders.

“What we discovered in this one disease,” points out Denise Horn from the Institute of Medical and Human Genetics at Charité — Universitätsmedizin Berlin, “might apply to many more disorders. 

“It is likely not a rare unicorn that exists only once. We just could not see the phenomenon until now because we did not know how to look for it.”

Working in collaboration with scientists from the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin, the University Hospital Schleswig-Holstein (UKSH), and other international contributors, the team is opening new avenues for diagnoses that could lead to a better understanding of many other diseases and potentially, future treatments.

Denes Hnisz, Research Group Leader at the MPIMG, claims to have uncovered a novel mechanism that might “be at play in a wide range of diseases, including hereditary diseases and cancer.” 

In fact, of the nearly 600 identical mutations that have been found, 101 have been linked to various illnesses.

According to human geneticist Malte Spielmann of UKSH in Lübeck and Kiel, “The actual work is just starting now,” and anticipated “find many more genes with such disease-causing mutations and can now test their mode of action.”

A strange mutation

People with “brachyphalangy-polydactyly-tibial aplasia/hypoplasia syndrome” have complex and striking malformations of the limbs, face, nervous system, and bone system, which are only partially described by the already long name of the disease (BPTAS).

The disorder is not just unusual “but ultra-rare,” according to Martin Mensah, a clinical geneticist at the Institute of Medical and Human Genetics at Charité, with less than ten recorded instances globally.

He and his team sequenced the genomes of five patients and discovered that all of them had mutations in the gene encoding the protein HMGB1.

This protein enhances the interaction of other molecules with the DNA, such as when reading genes, and organizes the genetic information in the cell nucleus.

If this gene is deleted from both chromosomes in mice, the result is embryonic death. However, the cells are employing the intact copy on the other chromosome in some individuals with just one copy of the mutation, leading to only a slight neurodevelopmental delay. However, the recently identified examples do not adhere to this pattern.

According to Mensah, a member of the Clinician Scientist Program run by the Berlin Institute of Health at Charité (BIH) and Charité, all five unrelated people showed the same ultra-rare illness and had practically the same mutation. 

“This is why we are sure that the HMGB1 mutation,” according to Mensah, “is the cause of the disease. However, at that point, we had no clue how the gene product functionally caused disease, especially given that loss-of-function mutations were reported to result in other phenotypes.”

Proteins with charged extensions

A detailed examination found that the effects of various HMGB1 mutations vary. The reading frame for the last third of the HMGB1 gene is displaced in those with severe abnormalities, according to the sequencing results.

Following protein translation, the appropriate area is now endowed with positively charged amino acid building blocks rather than negatively charged amino acid building blocks.

This may happen if the sequence lacks a number of genetic letters that is not divisible by three, since precisely three consecutive letters always code for one building block of the protein.

The protein’s tail, on the other hand, lacks a clear structure. Instead, this portion protrudes from the molecule like a loose rubber band.

It is challenging to investigate the functions of these protein tails, also known as “intrinsically disordered regions,” since often they only function when combined with other molecules. How may their mutation cause disease?

Droplets of protein in the cell

The medical researchers turned to MPIMG biochemists Denes Hnisz and Henri Niskanen, who specialize in cellular condensates that regulate critical genes, for a solution to this conundrum.

These droplet-like entities exhibit behavior like salad dressing’s oil and vinegar droplets. They are isolated from their environment, made up of a variety of distinct molecules, and capable of undergoing dynamic changes.

Niskanen thinks “condensates are formed in the cell for practical reasons.” 

In this approach, molecules for a certain purpose, like reading a gene, are clustered together. He estimates that several hundred proteins are involved in this process alone.

Niskanen uses the example of condensates to highlight the significance of the physical characteristics of the protein extensions in this context: “Intrinsically disordered regions, which tend not to have an obvious biochemical role, are thought to be responsible for forming condensates,”

“I can easily make a ball from many loose rubber bands that holds together relatively tightly and that can be taken apart with little effort. A ball of smooth fishing line or sticky tape, on the other hand, would behave quite differently.”

Solidifying droplets

Under a microscope, the condensate that makes up the nucleolus inside the cell’s nucleus appears as a diffusely dark speck. Many positively charged proteins tend to hang around in this area. This condensate is vital for cellular processes since many of these provide the machinery needed for protein synthesis.

Tests conducted with isolated protein as well as cell cultures revealed that the mutant protein HMGB1, which has a positively charged molecular tail, is also drawn to the nucleolus.

However, since the altered protein area has acquired an oily, adhesive component, it tends to clump. Niskanen was able to see with a microscope that the nucleolus loses its fluid-like properties and gets more solid.

This reduced the ability of the cells to carry out their essential duties; as a result, more cells in a culture containing the mutant protein perished than in a culture of unmutated cells.

Analysis of databases

The team then looked through databases of genomic data from thousands of people to see if there were any similar cases. In fact, the researchers were able to locate more than 600 such mutations in 66 proteins, each of which caused the reading frame of the protein to change and become both more positively charged and “greasy.” 101 of the variants were previously associated with several diseases.

The team chose 13 mutant genes for a test in cell culture. The mutant proteins preferred to localize in the nucleolus in 12 out of 13 instances. The nucleolus function was compromised by around half of the examined proteins, mirroring the BPTA syndrome’s illness mechanism.

New reasons for existing illnesses

Malte Spielmann, who led the study, says this “study could have an eye-opening effect. In the future, we can certainly elucidate the causes of some genetic diseases and hopefully one day treat them.”

But, even with this new knowledge, it’s “almost impossible to cure… congenital genetic diseases such as BPTAS,” according to Horn. 

“Because the malformations already develop in the womb, they would have to be treated with drugs before they develop. This would be very difficult to do.”

Hnisz adds that tumor illnesses are also largely genetically determined: “Cellular condensates and the associated phase separation are a fundamental mechanism of the cell that also plays a role in cancer. The chances of developing targeted therapies for this are much better.”

Source: 10.1038/s41586-022-05682-1

Image Credit: Sean Gallup/Getty Images

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