MSGID: 1:317/3 63e476f9   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Protein droplets may cause many types of genetic disease    
      
     Date:   
         February 8, 2023   
     Source:   
         Max-Planck-Gesellschaft   
     Summary:   
         Malfunction of cellular condensates is a disease mechanism relevant   
         for congenital malformations, common diseases, and cancer, new   
         research suggests.   
      
      
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   FULL STORY   
   ==========================================================================   
   Most proteins localize to distinct protein-rich droplets in cells, also   
   known as "cellular condensates." Such proteins contain sequence features   
   that function as address labels, telling the protein which condensate   
   to move into.   
      
   When the labels get screwed up, proteins may end up in the wrong   
   condensate.   
      
   According to an international team of researchers from clinical   
   medicine and basic biology, this could be the cause of many unresolved   
   diseases. The findings appeared in the journal Nature.   
      
      
   ==========================================================================   
   Patients with BPTA syndrome have characteristically malformed limbs   
   featuring short fingers and additional toes, missing tibia bones   
   in their legs and reduced brain size. As the researchers found out,   
   BPTAS is caused by a special genetic change that causes an essential   
   protein to migrate to the nucleolus, a large proteinaceous droplet in   
   the cell nucleus. As a result, the function of the nucleolar condensate   
   is inhibited and developmental disease develops.   
      
   "What we discovered in this one disease 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," says Denise Horn, a clinical geneticist at the Institute   
   of Medical and Human Genetics at Charite' -- Universita"tsmedizin Berlin.   
      
   In collaboration with scientists at the Max Planck Institute for Molecular   
   Genetics (MPIMG) in Berlin, the University Hospital Schleswig-Holstein   
   (UKSH), and contributors from all around the world, the team is pushing   
   open a door to new diagnoses that could lead to the elucidation of   
   numerous other diseases as well as possible future therapies.   
      
   "We discovered a new mechanism that could be at play in a wide range of   
   diseases, including hereditary diseases and cancer," says Denes Hnisz,   
   Research Group Leader at the MPIMG. "In fact, we have discovered over   
   600 similar mutations, 101 of which are known to be associated with   
   different disorders."  "The actual work is just starting now," adds human   
   geneticist Malte Spielmann of UKSH in Lu"beck and Kiel. "We will find   
   many more genes with such disease- causing mutations and can now test   
   their mode of action."  An unusual mutation Affected individuals have   
   complex and striking malformations of the limbs, face, and nervous and   
   bone systems, only partially described by the already- long disease name   
   "brachyphalangy-polydactyly-tibial aplasia/hypoplasia syndrome" (BPTAS).   
      
   "With fewer than ten documented cases worldwide, the disease is not   
   only rare, but ultra-rare," says Martin Mensah, clinical geneticist at   
   the Institute of Medical and Human Genetics at Charite'. To track down   
   the cause, he and his colleagues decoded the genome of five affected   
   individuals and found that the gene for the protein HMGB1 was altered   
   in all patients.   
      
   This protein has the task of organizing the genetic material in the cell   
   nucleus and facilitates the interaction of other molecules with the DNA,   
   for example to read genes.   
      
   In mice, a complete loss of the gene on both chromosomes is catastrophic   
   and leads to death of the embryo. In some patients with only one copy   
   mutated, however, the cells are using the intact copy on the other   
   chromosome, resulting only in mild neurodevelopmental delay. But the   
   newly discovered cases did not fit this scheme.   
      
   "All five unrelated individuals featured the same ultra-rare disorder   
   and had virtually the same mutation," says Mensah, who is a fellow   
   of the Clinician Scientist Program operated by the Berlin Institute   
   of Health at Charite' (BIH) and Charite'. "This is why we are sure   
   that the HMGB1 mutation 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."  Charged protein extensions A closer look revealed   
   that different mutations of HMGB1 have different consequences. The   
   sequencing data showed that in the affected individuals with the severe   
   malformations, the reading frame for the final third of the HMGB1 gene   
   is shifted.   
      
   After translation to protein, the corresponding region is now no longer   
   equipped with negative but with positively charged amino acid building   
   blocks.   
      
   This can happen if a number of genetic letters not divisible by three   
   is missing in the sequence, because exactly three consecutive letters   
   always code for one building block of the protein.   
      
   However, the tail part of the protein does not have a defined structure.   
      
   Instead, this section hangs out of the molecule like a loose rubber   
   band. The purposes of such protein tails (also called "intrinsically   
   disordered regions") are difficult to study because they often become   
   effective only in conjunction with other molecules. So how might their   
   mutation lead to the observed disease?  Protein droplets in the cell To   
   answer this question, the medical researchers approached biochemists Denes   
   Hnisz and Henri Niskanen at the MPIMG, who work with cellular condensates   
   that control important genes. These droplet-like structures behave   
   much like the oil and vinegar droplets in a salad dressing. Composed   
   of a large number of different molecules, they are separated from their   
   surroundings and can undergo dynamic changes.   
      
   "We think condensates are formed in the cell for practical reasons,"   
   Niskanen explains. Molecules for a specific task are grouped together   
   in this way, say to read a gene. For this task alone, he says, several   
   hundred proteins need to somehow make their way to the right place.   
      
   "Intrinsically disordered regions, which tend not to have an obvious   
   biochemical role, are thought to be responsible for forming condensates,"   
   Niskanen says, giving an example to describe how important the physical   
   properties of the protein extensions are in this regard. "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 The nucleolus within the cell   
   nucleus is also a condensate, which appears as a diffuse dark speck under   
   the microscope. This is where many proteins with positively charged tails   
   like to linger. Many of these provide the machinery required for protein   
   synthesis, making this condensate essential for cellular functions.   
      
   The mutant protein HMGB1 with its positively charged molecular tail is   
   attracted to the nucleolus as well, as the team observed from experiments   
   with isolated protein and with cell cultures.   
      
   But since the mutated protein region has also gained an oily, sticky   
   part, it tends to clump. The nucleolus loses its fluid-like properties   
   and increasingly solidifies, which Niskanen was able to observe under   
   the microscope. This impaired the vital functions of the cells -- with   
   the mutated protein, more cells in a culture died compared to a culture   
   of cells without the mutation.   
      
   Combing through databases The research team then searched databases   
   of genomic data from thousands of individuals looking for similar   
   incidents. In fact, the scientists were able to identify more than six   
   hundred similar mutations in 66 proteins, in which the reading frame   
   had been shifted by a mutation in the protein tail, making it both more   
   positively charged and more "greasy." Of the mutations, 101 had previously   
   been linked to several different disorders.   
      
   For a cell culture assay, the team selected 13 mutant genes. In 12   
   out of 13 cases, the mutant proteins had a preference to localize into   
   the nucleolus.   
      
   About half of the tested proteins impaired the function of the nucleolus,   
   resembling the disease mechanism of BPTA syndrome.   
      
   New explanations for existing diseases "For clinical research, our study   
   could have an eye-opening effect," says Malte Spielmann, who led the   
   research together with Denes Hnisz and Denise Horn. "In the future, we   
   can certainly elucidate the causes of some genetic diseases and hopefully   
   one day treat them."  However, "congenital genetic diseases such as   
   BPTAS are almost impossible to cure even with our new knowledge," says   
   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."  But tumor diseases are also predominantly genetically   
   determined, adds Hnisz: "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."   
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Genes # Human_Biology # Diseases_and_Conditions #   
                   Gene_Therapy # Personalized_Medicine # Nervous_System #   
                   Sickle_Cell_Anemia # Lymphoma   
       * RELATED_TERMS   
             o Breast_cancer o COPD o Arthritis o HPV_vaccine o   
             Stem_cell_treatments o Vaccination o Cervical_cancer o   
             Colorectal_cancer   
      
   ==========================================================================   
   Story Source: Materials provided by Max-Planck-Gesellschaft. Note:   
   Content may be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Martin A. Mensah, Henri Niskanen, Alexandre P. Magalhaes,   
      Shaon Basu,   
         Martin Kircher, Henrike L. Sczakiel, Alisa M. V. Reiter, Jonas   
         Elsner, Peter Meinecke, Saskia Biskup, Brian H. Y. Chung, Gregor   
         Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander   
         Hoischen, Paul- Martin Holterhus, Wiebke Hu"lsemann, Kimia Kahrizi,   
         Vera M. Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas   
         Leubner, Ann Carolin Longardt, Jo"rg D. Moritz, Hossein Najmabadi,   
         Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard   
         Wiedersberg, Martin Zenker, Carla Garcia-Cabau, Rene' Buschow,   
         Xavier Salvatella, Matthew L.   
      
         Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann,   
         Denise Horn, Denes Hnisz. Aberrant phase separation and   
         nucleolar dysfunction in rare genetic diseases. Nature, 2023;   
         DOI: 10.1038/s41586-022-05682-1   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/02/230208155720.htm   
      
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