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

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) i s a rare, apparently monogenic, autosomal recessive disorder characterized by recurrent episodes of fever accompanied with lymphadenopathy, abdominal distress,joint involvement and skin lesions'.;All patients have high serum IgD values (>100 U/ml) and HIDS 'attacks' are associated with an intense ac ute phase reaction whose exact pathophysiology remains obscure(2-4). Two ot her hereditary febrile disorders have been described. Familial Mediterranea n fever (MIM 249100) is an autosomal recessive disorder affecting mostly po pulations from the Mediterranean basin and is caused by mutations in the ge ne MEFV(refs 5,6). Familial Hibernian fever (MIM 142680), also known as aut osomal: dominant familial recurrent-fever, is caused by missense mutations in the gene encoding type 1 tumour necrosis factor receptor(7-10). Here we perform a genome-wide search to map the HIDS; gene. Haplotype analysis:plac ed the gene at 12q24 between D12S330 and D12S79. We identified the gene MVK ,: encoding mevalonate kinase (MK, ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36), 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 ac tivity in: fibroblasts from HIDS-patients. Our data establish MVK as the: g ene responsible for HIDS.