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Study: Enzyme increases risk of developing Crohn’s disease, Still’s disease and leprosy

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(Vienna, 24-01-2020) The risk of developing an autoimmune disease is largely influenced by environmental factors, lifestyle and genetic factors. It was already known that mutations in the FAMIN gene are associated with an increased risk of developing Crohn's disease, Still's disease and leprosy but the exact role of the protein was not known. An international research group including MedUni Vienna has identified this role and has shown that, as an enzyme in the purine metabolism, FAMIN regulates cellular energy management, thereby influencing the risk of disease.

Despite constant improvements in our understanding of the causes of certain diseases, there is little understanding of the precise mechanisms, such as genetic variants, that contribute to the onset of diseases. The FAMIN gene (Lacc1, C13orf31) contains several of the variants that increase the risk of developing Crohn's disease, Still's disease and leprosy. With the assistance of Lukas Unger (Division of General Surgery, MedUni Vienna), the research group led by Arthur Kaser (Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge) has now identified the role of the protein and made the connection between mutations and protein function.

In the paper, which was published in the leading journal "Cell", the authors show that FAMIN is a new type of enzyme in the purine metabolism that regulates the rate of cell metabolism via the metabolisation of nucleosides. FAMIN combines three responses of the central purine metabolism. FAMIN's substrates – adenine and ribose phosphate – are not only the central component of DNA and RNA and of the cells' energy store (ATP) but probably the metabolite from which life emerged from prebiotic chemistry.

"FAMIN actually seems to be a very' old' enzyme," explains Lukas Unger from MedUni Vienna's Department of Surgery, who is currently researching as a post-doc at the University of Cambridge, "it stands for a new class of proteins which has been evolutionarily conserved from bacteria through to humans. In immune cells, FAMIN regulates the activity of glucose oxidation and of energy metabolism in mitochondria, the power stations of the cells."

Disease-associated genetic variants of FAMIN lead to reduced elimination of germs and a modified release of immune system messenger substances. "The results of our study show how genetic variants of a metabolic enzyme can lead to the development of autoimmune diseases in the gut and the joints," says Unger.

Service: Cell
Cader et al., FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle, Cell (2020),