Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome
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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-α 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.
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- Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome
Journal of Inherited Metabolic Disease
Volume 30, Issue 6 , pp 888-895
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- 1. Division of Medical Genetics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Rangos Research Building, Room 2113, 3460 Fifth Ave., Pittsburgh, PA, 15213, USA
- 2. Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- 3. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
- 10. Genome Manipulation Facility, Harvard Stem Cell Institute and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
- 4. Department of Comparative Medicine, Oregon Health & Science University, Portland, OR, USA
- 5. Department of Medicine, Oregon Health & Science University, Portland, OR, USA
- 6. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
- 7. Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA
- 8. Department of Pediatrics, University of Heidelberg, Heidelberg, Germany
- 9. Department of Pathology, Biochemical Genetics/Nutrition Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA