Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome

In the current study our objective was to develop a murine model of human hyper-IgD syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase deficiency (MKD). Deletion of one Mvk allele (Mvk(+/-)) yielded viable mice with significantly reduced liver Mvk enzyme activity; multiple matings failed to produce Mvk(-/-) mice. Cholesterol levels in tissues and blood, and isoprene end-products (ubiquinone, dolichol) in tissues were normal in Mvk(+/-) mice; conversely, mevalonate concentrations were increased in spleen, heart, and kidney yet normal in brain and liver. While the trend was for higher IgA levels in Mvk(+/-) sera, IgD levels were significantly increased (9-12-fold) in comparison to Mvk(+/+) littermates, in both young (< 15 weeks) and older (> 15 weeks) mice. Mvk(+/-) animals manifested increased serum TNF-alpha as compared to wild-type littermates, but due to wide variation in levels between individual Mvk(+/-) mice the difference in means was not statistically significant. Mvk(+/-) mice represent the first animal model of HIDS, and should prove useful for examining pathophysiology associated with this disorder.