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

Nature Genetics volume 22, pages 175177 (1999) | Download Citation

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

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DOI

https://doi.org/10.1038/9691

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