title: Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome.
abstract: 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.
authors.affiliation: 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.
authors.forename: E J
authors.initials: EJ
authors.lastname: Hager
authors.forename: H M
authors.initials: HM
authors.lastname: Tse
authors.forename: J D
authors.initials: JD
authors.lastname: Piganelli
authors.forename: M
authors.initials: M
authors.lastname: Gupta
authors.forename: M
authors.initials: M
authors.lastname: Baetscher
authors.forename: T E
authors.initials: TE
authors.lastname: Tse
authors.forename: A S
authors.initials: AS
authors.lastname: Pappu
authors.forename: R D
authors.initials: RD
authors.lastname: Steiner
authors.forename: G F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: K M
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D004286:Dolichols / Q000737:chemistry; D017353:Gene Deletion; D005787:Gene Frequency; D006801:Humans; D007072:Immunoglobulin D / Q000737:chemistry; D054078:Mevalonate Kinase Deficiency / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D014451:Ubiquinone / Q000737:chemistry
chemical_list: D004286:Dolichols; D007072:Immunoglobulin D; D014451:Ubiquinone; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase