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Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome

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Abstract

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash1,2. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels2. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.

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Figure 1: Expression of MVK cDNAs in E.coli.
Figure 2: Immunoblot analysis of fibroblast lysates of HIDS patients.

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References

  1. van der Meer, J.W.M. et al. Hyperimmunoglobulinemia D and periodic fever: a new syndrome. Lancet 1, 1087– 1090 (1984).

    Article  CAS  Google Scholar 

  2. Drenth, J.P.H., Haagsma, C.J., van der Meer, J.W.M. & The International Hyper-IgD Study Group Hyperimmunoglobulinemia D and periodic fever syndrome: the clinical spectrum in a series of 50 patients. Medicine 73, 133–144 (1994).

    Article  CAS  Google Scholar 

  3. Biardi, L. et al. Mevalonate kinase is predominantly localized in peroxisomes and is defective in patients with peroxisomal disorders. J. Biol. Chem. 269, 1197–1205 ( 1994).

    CAS  PubMed  Google Scholar 

  4. Goldstein, J.L. & Brown, M.S. Regulation of the mevalonate pathway. Nature 343, 425– 430 (1990).

    Article  CAS  Google Scholar 

  5. Hoffmann, G. et al. Mevalonic aciduria—an inborn error of cholesterol and nonsterol isoprene biosynthesis. N. Engl. J. Med. 314 , 1610–1614 (1986).

    Article  CAS  Google Scholar 

  6. Hoffmann, G.F. et al. Clinical and biochemical phenotype in 11 patients with mevalonic aciduria. Pediatrics 91, 915– 921 (1993).

    CAS  PubMed  Google Scholar 

  7. Schafer, B.L. et al. Molecular cloning of human mevalonate kinase and identification of a missense mutation in the genetic disease mevalonic aciduria. J. Biol. Chem. 267, 13229–13238 (1992).

    CAS  PubMed  Google Scholar 

  8. Hinson, D.D. et al. Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency. J. Biol. Chem. 272, 26756– 26760 (1997).

    Article  CAS  Google Scholar 

  9. Centola, M., Aksentijevich, I. & Kastner, D.L. The hereditary periodic fever syndromes: molecular analysis of a new family of inflammatory diseases. Hum. Mol. Genet. 7, 1581–1588 ( 1998).

    Article  CAS  Google Scholar 

  10. Lindenthal, B. et al. Urinary excretion of mevalonic acid as an indicator of cholesterol synthesis. J. Lipid Res. 37, 2193– 2201 (1996).

    CAS  PubMed  Google Scholar 

  11. Hoffmann, G.F. et al. Mevalonate kinase assay using DEAE-cellulose column chromatography for first-trimester prenatal diagnosis and complementation analysis in mevalonic aciduria. J. Inherit. Metab. Dis. 15, 738 –746 (1992).

    Article  CAS  Google Scholar 

  12. Habig, W.H., Pabst, M.J. & Jakoby, W.B. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J. Biol. Chem. 249, 7130–7139 (1974).

    CAS  PubMed  Google Scholar 

  13. Ijlst, L., Wanders, R.J.A., Ushikubo, S., Kamijo, T. & Hashimoto, T. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the α-subunit of the mitochondrial trifunctional protein. Biochim. Biophys. Acta 1215, 347– 350 (1994).

    Article  Google Scholar 

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Authors and Affiliations

  1. Departments of Clinical Chemistry and Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam;,

    Sander M. Houten, Gerrit J. Romeijn, Hans R. Waterham & Ronald J.A. Wanders

  2. Departments of Immunology, University Children's Hospital "Het Wilhelmina Kinderziekenhuis", Utrecht

    Wietse Kuis, Annet van Royen-Kerkhof & Ger T. Rijkers

  3. Metabolic Disorders, University Children's Hospital "Het Wilhelmina Kinderziekenhuis", Utrecht

    Marinus Duran, Tom J. de Koning, Lambertus Dorland, Martina M.J. de Barse & Bwee Tien Poll-The

  4. General Pediatrics, University Children's Hospital "Het Wilhelmina Kinderziekenhuis", Utrecht

    Joost Frenkel

  5. Beatrix Hospital, Gorinchem, The Netherlands

    Wim A.R. Huijbers

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  1. Sander M. Houten
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  2. Wietse Kuis
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  3. Marinus Duran
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  4. Tom J. de Koning
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  5. Annet van Royen-Kerkhof
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  6. Gerrit J. Romeijn
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  7. Joost Frenkel
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  8. Lambertus Dorland
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  9. Martina M.J. de Barse
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  10. Wim A.R. Huijbers
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  11. Ger T. Rijkers
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  12. Hans R. Waterham
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  13. Ronald J.A. Wanders
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  14. Bwee Tien Poll-The
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Corresponding authors

Correspondence to Hans R. Waterham or Bwee Tien Poll-The.

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Houten, S., Kuis, W., Duran, M. et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet 22, 175–177 (1999). https://doi.org/10.1038/9691

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  • DOI: https://doi.org/10.1038/9691

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