Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Mutations of MVK.

References

  1. 1

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

  2. 2

    Drenth, J.P., Powell, R.J., Brown, N.S. & van der Meer, J.W. Interferon-γ and urine neopterin in attacks of the hyperimmunoglobulinaemia D and periodic fever syndrome. Eur. J. Clin. Invest. 25, 683–686 (1995).

  3. 3

    Drenth, J.P., van der Meer, J.W. & Kushner, I. Unstimulated peripheral blood mononuclear cells from patients with the hyper-IgD syndrome produce cytokines capable of potent induction of C-reactive protein and serum amyloid A in Hep3B cells. J. Immunol. 157, 400–404 ( 1996).

  4. 4

    Drenth, J.P., van Deuren, M., van der Ven-Jongekrijg, J., Schalkwijk, C.G. & van der Meer, J.W. Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood 85, 3586– 3593 (1995).

  5. 5

    A candidate gene for familial Mediterranean fever. The French FMF Consortium. Nature Genet. 17, 25–31 (1997).

  6. 6

    Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 90, 797– 807 (1997).

  7. 7

    McDermott, M.F. et al. Linkage of familial Hibernian fever to chromosome 12p13. Am. J. Hum. Genet. 62, 1446–1451 (1998).

  8. 8

    Mulley, J. et al. Gene localization for an autosomal dominant familial periodic fever to 12p13. Am. J. Hum. Genet. 62, 884 –889 (1998).

  9. 9

    McDermott, E.M., Smillie, D.M. & Powell, R.J. Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family. Mayo Clin. Proc. 72, 806–817 ( 1997).

  10. 10

    McDermott, M.F. et al. Germline mutations in the extracellular domains of the 55kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133– 144 (1999).

  11. 11

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

  12. 12

    Potter, D., Wojnar, J.M., Narasimhan, C. & Miziorko, H.M. Identification and functional characterization of an active-site lysine in mevalonate kinase. J. Biol. Chem. 272, 5741 –5746 (1997).

  13. 13

    Potter, D. & Miziorko, H.M. Identification of catalytic residues in human mevalonate kinase. J. Biol. Chem. 272, 25449–25454 (1997).

  14. 14

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

  15. 15

    Yamagishi, A. et al. Mucopolysaccharidosis type I: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations. Hum. Mutat. 7, 23–29 ( 1996).

  16. 16

    Drenth, J.P., Mariman, E.C., Van der Velde-Visser, S.D., Ropers, H.H. & van der Meer, J.W. Location of the gene causing hyperimmunoglobulinemia D and periodic fever syndrome differs from that for familial Mediterranean fever. International Hyper-IgD Study Group. Hum. Genet. 94, 616–620 (1994).

  17. 17

    Reed, P.W. et al. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nature Genet. 7, 390–395 (1994).

  18. 18

    Ott, J. Computer-simulation methods in human linkage analysis. Proc. Natl Acad. Sci. USA 86, 4175–4178 (1989).

  19. 19

    Cottingham, R.W. Jr, Idury, R.W. & Schafer, A.A. Faster sequential genetic linkage computation. Am. J. Hum. Genet. 53, 252– 263 (1993).

  20. 20

    Ott, J. Analysis of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1991).

  21. 21

    Gibson, K.M. et al. Mevalonate kinase in lysates of cultured human fibroblasts and lymphoblasts: kinetic properties, assay conditions, carrier detection and measurement of residual activity in a patient with mevalonic aciduria. Enzyme 41, 47–55 (1989).

Download references

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.

Author information

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading