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

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Journal of Inherited Metabolic Disease

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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References

  • Drenth JP, Haagsma CJ, van der Meer JW (1994) Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine 73: 133-44.

    Article  CAS  PubMed  Google Scholar 

  • Drenth JP, Cuisset L, Grateau G, et al (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 22: 178-81.

    Article  CAS  PubMed  Google Scholar 

  • Ghittoni R, Napolitani G, Benati D, et al (2006) Simvastatin inhibits the MHC class II pathway of antigen presentation by impairing Ras superfamily GTPases. Eur J Immunol 36: 2885-893.

    Article  CAS  PubMed  Google Scholar 

  • Gibson KM, Hoffmann G, Nyhan WL, et al (1988) Mevalonate kinase deficiency in a child with cerebellar ataxia, hypotonia and mevalonic aciduria. Eur J Pediatr 148: 250-52.

    Article  CAS  PubMed  Google Scholar 

  • Gibson KM, Gupta M, Baetscher M, Steiner RD, Hoffmann GF, Hager EJ (2006) Early embryonic lethality associated with targeted disruption of the murine mevalonate kinase gene. J Inherit Metab Dis 29(Supplement 1): 50 [abstract].

    Google Scholar 

  • Gibson KM, Tse TE, Pappu AS, Steiner RD, Hoffmann GF, Hager EJ (2007) Chronic inflammation and hyper IgD/IgE in mice with targeted deletion of the mevalonate kinase. (Mvk) gene. J Inherit Metab Dis 30(Supplement 1): 45 [abstract].

    Google Scholar 

  • Hillyard DZ, Jardine AG, McDonald KJ, Cameron AJ (2004) Fluvastatin inhibits raft dependent Fcgamma receptor signalling in human monocytes. Atherosclerosis 172: 219-28.

    Article  CAS  PubMed  Google Scholar 

  • Hinson DD, Chambliss KL, Toth MJ, Tanaka RD, Gibson KM (1997) Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways. J Lipid Res 38: 2216-223.

    CAS  PubMed  Google Scholar 

  • Hoffmann G, Gibson KM, Brandt IK, Bader PI, Wappner RS, Sweetman L (1986) Mevalonic aciduria—an inborn error of cholesterol and nonsterol isoprene biosynthesis. N Engl J Med 314: 1610-614.

    Article  CAS  PubMed  Google Scholar 

  • Hogema BM, Gupta M, Senephansiri H, et al (2001) Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet 29: 212-16.

    Article  CAS  PubMed  Google Scholar 

  • Houten SM, Frenkel J, Rijkers GT, Wanders RJ, Kuis W, Waterham HR (2002) Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome. Hum Mol Genet 11: 3115-124.

    Article  CAS  PubMed  Google Scholar 

  • Hubner C, Hoffmann GF, Charpentier C, et al (1993) Decreased plasma ubiquinone-10 concentration in patients with mevalonate kinase deficiency. Pediatr Res 34: 129-33.

    Article  CAS  PubMed  Google Scholar 

  • Klasen IS, Goertz JH, van de Wiel GA, Weemaes CM, van der Meer JW, Drenth JP (2001) Hyperimmunoglobulin A in the hyperimmunoglobulinemia. D syndrome. Clin Diagn Lab Immunol 8: 58-1.

    CAS  PubMed  Google Scholar 

  • Mandey SH, Schneiders MS, Koster J, Waterham HR (2006a) Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat 27: 796-02.

    Article  CAS  PubMed  Google Scholar 

  • Mandey SH, Kuijk LM, Frenkel J, Waterham HR (2006b) A role for geranylgeranylation in interleukin-1beta secretion. Arthritis Rheum 54: 3690-695.

    Article  CAS  PubMed  Google Scholar 

  • Ness GC, Chambers CM (2000) Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med 224: 8-9.

    Article  CAS  PubMed  Google Scholar 

  • Neven B, Valayannopoulos V, Quartier P, et al (2007) Allogenic bone marrow transplantation in mevalonic aciduria. N Engl J Med 356: 2700-703.

    Article  CAS  PubMed  Google Scholar 

  • Ohashi K, Osuga J-i, Tozawa R, et al (2003) Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. J Biol Chem 278: 42936-2941.

    Article  CAS  PubMed  Google Scholar 

  • Okamoto T, Fukunaga Y, Ida Y, Kishi T (1988) Determination of reduced and total ubiquinones in biological materials by liquid chromatography with electrochemical detection. J Chromatogr 430: 11-9.

    Article  CAS  PubMed  Google Scholar 

  • Pappu AS, Illingworth DR, Bacon S (1989) Reduction in plasma low-density lipoprotein cholesterol and urinary mevalonic acid by lovastatin in patients with heterozygous familial hypercholesterolemia. Metabolism 38: 542-49.

    Article  CAS  PubMed  Google Scholar 

  • Pappu AS, Connor WE, Merkens LS, et al (2006) Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith–Lemli–Opitz syndrome: effects of dietary cholesterol. J Lipid Res 47: 2789-798.

    Article  CAS  PubMed  Google Scholar 

  • Prietsch V, Mayatepek E, Krastel H, et al (2003) Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum. Pediatrics 111: 258-61.

    Article  PubMed  Google Scholar 

  • Rios SE, Cho YK, Miziorko HM (2001) Characterization of mevalonate kinase V377I, a mutant implicated in defective isoprenoid biosynthesis and HIDS/periodic fever syndrome. Biochim Biophys Acta 1531: 165-68.

    CAS  PubMed  Google Scholar 

  • Tozawa R-i, Ishibashi S, Osuga J-i, et al (1999) Embryonic lethality and defective neural tube closure in mice lacking squalene synthase. J Biol Chem 274: 30843-0848.

    Article  CAS  PubMed  Google Scholar 

  • Turpeinen U (1986) Liquid-chromatographic determination of dolichols in urine. Clin Chem 32: 2026-029.

    CAS  PubMed  Google Scholar 

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Author information

Author notes

  1. M. Baetscher

    Present address: Genome Manipulation Facility, Harvard Stem Cell Institute and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA

Authors and Affiliations

  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

    E. J. Hager, T. E. Tse & K. M. Gibson

  2. Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    H. M. Tse & J. D. Piganelli

  3. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA

    M. Gupta, M. Baetscher & R. D. Steiner

  4. Department of Comparative Medicine, Oregon Health & Science University, Portland, OR, USA

    M. Baetscher

  5. Department of Medicine, Oregon Health & Science University, Portland, OR, USA

    A. S. Pappu

  6. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    R. D. Steiner

  7. Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, OR, USA

    R. D. Steiner

  8. Department of Pediatrics, University of Heidelberg, Heidelberg, Germany

    G. F. Hoffmann

  9. Department of Pathology, Biochemical Genetics/Nutrition Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    K. M. Gibson

Authors
  1. E. J. Hager
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  2. H. M. Tse
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  3. J. D. Piganelli
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  4. M. Gupta
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  5. M. Baetscher
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  6. T. E. Tse
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  7. A. S. Pappu
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  8. R. D. Steiner
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  9. G. F. Hoffmann
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  10. K. M. Gibson
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Corresponding author

Correspondence to K. M. Gibson.

Additional information

Communicating editor: Johannes Zschocke

Competing interests: None declared

References to electronic databases: Mevalonate kinase: EC 2.7.1.36; OMIM 610377;251170;260920.

This paper has been presented in abstract form (Gibson et al 2006, 2007).

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Hager, E.J., Tse, H.M., Piganelli, J.D. et al. Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome. J Inherit Metab Dis 30, 888–895 (2007). https://doi.org/10.1007/s10545-007-0776-7

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  • DOI: https://doi.org/10.1007/s10545-007-0776-7

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