Journal of Inherited Metabolic Disease

, Volume 30, Issue 6, pp 888–895

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

  • E. J. Hager
  • H. M. Tse
  • J. D. Piganelli
  • M. Gupta
  • M. Baetscher
  • T. E. Tse
  • A. S. Pappu
  • R. D. Steiner
  • G. F. Hoffmann
  • K. M. Gibson
Rapid Communication

Summary

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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Copyright information

© SSIEM and Springer 2007

Authors and Affiliations

  • E. J. Hager
    • 1
  • H. M. Tse
    • 2
  • J. D. Piganelli
    • 2
  • M. Gupta
    • 3
  • M. Baetscher
    • 3
    • 4
    • 10
  • T. E. Tse
    • 1
  • A. S. Pappu
    • 5
  • R. D. Steiner
    • 3
    • 6
    • 7
  • G. F. Hoffmann
    • 8
  • K. M. Gibson
    • 1
    • 9
  1. 1.Division of Medical Genetics, Children’s Hospital of PittsburghUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of PittsburghUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of Molecular and Medical GeneticsOregon Health & Science UniversityPortlandUSA
  4. 4.Department of Comparative MedicineOregon Health & Science UniversityPortlandUSA
  5. 5.Department of MedicineOregon Health & Science UniversityPortlandUSA
  6. 6.Department of PediatricsOregon Health & Science UniversityPortlandUSA
  7. 7.Oregon Clinical and Translational Research InstituteOregon Health & Science UniversityPortlandUSA
  8. 8.Department of PediatricsUniversity of HeidelbergHeidelbergGermany
  9. 9.Department of Pathology, Biochemical Genetics/Nutrition LaboratoryUniversity of Pittsburgh School of MedicinePittsburghUSA
  10. 10.Genome Manipulation Facility, Harvard Stem Cell Institute and Department of Molecular and Cellular BiologyHarvard UniversityCambridgeUSA

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