Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome (original) (raw)

Nature Genetics volume 22, pages 178–181 (1999)Cite this article

Abstract

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is a rare, apparently monogenic, autosomal recessive disorder characterized by recurrent episodes of fever accompanied with lymphadenopathy, abdominal distress, joint involvement and skin lesions1. All patients have high serum IgD values (>100 U/ml) and HIDS 'attacks' are associated with an intense acute phase reaction whose exact pathophysiology remains obscure2,3,4. Two other hereditary febrile disorders have been described. Familial Mediterranean fever (MIM 249100) is an autosomal recessive disorder affecting mostly populations from the Mediterranean basin and is caused by mutations in the gene MEFV (Refs 5,6). Familial Hibernian fever (MIM 142680), also known as autosomal dominant familial recurrent fever, is caused by missense mutations in the gene encoding type I tumour necrosis factor receptor7,8,9,10. Here we perform a genome-wide search to map the HIDS gene. Haplotype analysis placed the gene at 12q24 between D12S330 and D12S79. We identified the gene MVK, encoding mevalonate kinase (MK, ATP:mevalonate 5-phosphotransferase; EC 2.7.I.36), as a candidate gene. We characterized 3 missense mutations, a 92-bp loss stemming from a deletion or from exon skipping, and the absence of expression of one allele. Functional analysis demonstrated diminished MK activity in fibroblasts from HIDS patients. Our data establish MVK as the gene responsible for HIDS.

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Figure 1: Mutations of MVK.

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Acknowledgements

We thank patients for cooperation and the following members of the International Hyper-IgD Study Group for collecting blood from patients: C.M.R. Weemaes, C.D.A. Stehouwer, E.R. de Graeff-Meeder, R.J. Powell, T. Espanol, D. Jílek, J.Mydlil, S. Kynclova, V. Kredbova, A.M. Prieur, A. Metton, P. Le Touze, J.P. Dommergues, M. Alcalay, C. Chapelon-Abric and J. Louis. We thank S. Pavek for technical support; M.O. Rolland for mevalonate kinase assays; F. Letourneur for sequencing; and J.C. Barbot for SSCP. J.P.H.D. is a recipient of a grant from the Niels Stensen Foundation and a travel grant from the Netherlands Organisation of Scientific Research (F92-189). Part of this work has been supported by the Association Française contre les Myopathies.

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Author notes

  1. Joost P.H. Drenth and Laurence Cuisset: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratoire de Génétique Moléculaire Humaine, Institut Cochin de Génétique Moléculaire (ICGM) and Hôpital Cochin, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France
    Joost P.H. Drenth, Laurence Cuisset, Christian Vasseur & Marc Delpech & contributing members of the International Hyper-IgD Study Group
  2. Department of Medicine, Division of General Internal Medicine, University Hospital St. Radboud, Nijmegen, The Netherlands
    Joost P.H. Drenth & Jos W.M. van der Meer
  3. Service de Médecine Interne, L'Hôtel-Dieu (AP-HP), Paris, France
    Gilles Grateau
  4. Department of Human Genetics, University Hospital St. Radboud, Nijmegen, The Netherlands
    Saskia D. van de Velde-Visser
  5. Laboratory of Pediatrics and Neurology University Hospital St. Radboud, Nijmegen, The Netherlands
    Jan G.N. de Jong
  6. URA CNRS 1922 Généthon et Centre National de Génotypage, Evry, France
    Jacques S. Beckmann

Authors

  1. Joost P.H. Drenth
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  2. Laurence Cuisset
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  3. Gilles Grateau
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  4. Christian Vasseur
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  5. Saskia D. van de Velde-Visser
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  6. Jan G.N. de Jong
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  7. Jacques S. Beckmann
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  8. Jos W.M. van der Meer
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  9. Marc Delpech & contributing members of the International Hyper-IgD Study Group
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Corresponding author

Correspondence toMarc Delpech & contributing members of the International Hyper-IgD Study Group.

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Drenth, J., Cuisset, L., Grateau, G. et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome.Nat Genet 22, 178–181 (1999). https://doi.org/10.1038/9696

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