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Content Posted in | Providence Digital Commons

Pediatric Rheumatology volume 17 , Article number: 18 Cite this article. Metrics details. Introduction: Mevalonate Kinase Deficiency MKD is a periodic fever syndrome characterised by recurrent bouts of high fever and systemic inflammation. MKD is caused by recessive, hypomorphic mutations in the mevalonate kinase gene MVK encoding a key enzyme in the mevalonate pathway. This pathway is responsible for cholesterol synthesis and the production of isoprenoid lipid tags required for post-translational prenylation of proteins.

It is believed that inflammation in MKD is triggered by shortage of isoprenoid lipids and defective prenylation of small GTPases. We have found that protein prenylation is indeed compromised in PBMCs from patients and this defect distinguishes MKD from other periodic fever syndromes. However, the link between protein prenylation and inflammation in MKD is still far from understood, largely due to the lack of suitable genetic mouse models.

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To assess the effect of the mutations on the mevalonate pathway, we measured the accumulation of unprenylated Rab GTPases and Rap1A using an in vitro prenylation assay and western blotting. Results: Homozygous mice carrying complete loss of function deletion mutations were not viable and, as expected, wildtype and heterozygous Mvk mutant mice had normal protein prenylation.

This is consistent with reportedly less severe clinical disease associated with the homozygous VI mutation. Interestingly, like patient-derived cell lines, the prenylation defect was dramatically enhanced in bone marrow cells from Mvk mutant mice after briefly culturing at higher temperature o C.

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Importantly, addition of the missing isoprenoid lipid geranylgeraniol could rescue the prenylation defect in primary cell cultures in vitro and in peritoneal macrophages in vivo. Conclusion: To our knowledge, we have generated the first genetic mouse avatars of MKD.

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