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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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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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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