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Untethered Proteins Could Help Diagnose MKD

By Labmedica International staff writers
Posted on 30 May 2017
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Image: A new study shows untethered Rab proteins are found only in people in MKD, leading to the potential for early diagnosis of the disease (Photo courtesy of Getty Images).
Image: A new study shows untethered Rab proteins are found only in people in MKD, leading to the potential for early diagnosis of the disease (Photo courtesy of Getty Images).
Mevalonate Kinase Deficiency (MKD), also known as HIDS (hyper IgD syndrome), is a rare genetic condition that affects approximately 200 individuals worldwide. It is a spectrum of disease, with complications that range from mild to severe. MKD is one of more than 8,000 known rare and genetic conditions, which, although individually uncommon, collectively affect up to 10% of the population.

Individuals with MKD experience recurrent and frequent attacks of high fever, which are associated with pain in the joints, muscles and abdomen, along with skin rash. Attacks of fever can last for several days and occur periodically throughout life. In its severest form, also known as mevalonic aciduria, MKD can be life-threatening, and can involve neurological symptoms and impaired growth.

Scientists at the Garvan Institute of Medical Research developed a highly sensitive in vitro prenylation assay that enables the detection of unprenylated small GTPase proteins in cell lysates. Human peripheral blood monocytes (PBMCs) were isolated from buffy coat preparations of fresh blood samples and cell pellets were snap frozen before analysis. The scientists performed Western blots and in vitro prenylated (i.e., biotinylated) proteins were detected on polyvinylidene difluoride blots using streptavidin-680RD. Blots were also analyzed for unprenylated Rap1A using goat anti-Rap1A.

The team showed that, within the cells, several proteins from the same family (known as Rab proteins) had no isoprenoid 'tail', a molecule that is usually added to these proteins in the final stages of preparing them for their work in the cell. An isoprenoid tail is thought to act as a molecular 'tether' for the protein it is attached to. The isoprenoid tails on Rab proteins keep them in a particular area of the cell close to the cell membrane. Without their tethers, the Rab proteins, and other related proteins, are 'on the loose' in the cells of children with MKD, and are free to move into other parts of the cell. It is thought that this could set off the disease process in MKD, triggering inflammation. Untethered Rab proteins are found only in people in MKD. They are not present in the cells of people with other rare diseases that have similar clinical symptoms (the periodic fever syndromes) or in the parents of children with MKD.

Michael J. Rogers, PhD, a professor and chief investigator, said, “It has been thought for some time that individuals with MKD might have untethered Rab proteins, because we know that a gene called mevalonate kinase (MVK), which is altered in MKD, is important in making the isoprenoid tails that are fitted onto these proteins. Until now, though, no one has been able to show that these untethered proteins do in fact build up in the cells of kids with MKD. To see these proteins directly, and to show that they are lacking their ‘tails’ is an important advance in our understanding of this devastating disease.” The study was published on May 10, 2017, in the Journal of Allergy and Clinical Immunology.


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