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

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) i s an autosomal recessive disorder characterized by recurrent episodes of fe ver associated with lymphadenopathy, arthralgia, gastrointestinal dismay an d skin rash(1,) (2). Diagnostic hallmark of HIDS is a constitutively elevat ed level of serum immunoglobulin D (IgD), although patients have been repor ted with normal IgD levels'. 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 re duced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the p atients identified three different mutations, one of which was common to al l 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 fibr oblasts, indicating a protein-destabilizing effect of the mutations.