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Deletion of a single mevalonate kinase ( Mvk ) allele yields a murine model of hyper‐IgD syndrome
Author(s) -
Hager E. J.,
Tse H. M.,
Piganelli J. D.,
Gupta M.,
Baetscher M.,
Tse T. E.,
Pappu A. S.,
Steiner R. D.,
Hoffmann G. F.,
Gibson K. M.
Publication year - 2007
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-007-0776-7
Subject(s) - immunoglobulin d , allele , genetics , biology , gene , antibody , b cell
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.