Houten S M, Kuis W, Duran M, de Koning T J, van Royen-Kerkhof A, Romeijn G J, Frenkel J, Dorland L, de Barse M M, Huijbers W A, Rijkers G T, Waterham H R, Wanders R J, Poll-The B T
Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands.
Nat Genet. 1999 Jun;22(2):175-7. doi: 10.1038/9691.
Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported 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 reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all 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 fibroblasts, indicating a protein-destabilizing effect of the mutations.
高免疫球蛋白D血症和周期性发热综合征（HIDS；MIM 260920）是一种常染色体隐性疾病，其特征为反复发热发作，并伴有淋巴结病、关节痛、胃肠不适和皮疹。HIDS的诊断标志是血清免疫球蛋白D（IgD）水平持续升高，不过也有患者报告IgD水平正常。为了确定HIDS的潜在缺陷，我们分析了数名患者的尿液，发现在严重发热发作期间甲羟戊酸浓度升高，而在发作间期则未升高。随后对4名无亲缘关系的HIDS患者的细胞进行分析，发现甲羟戊酸激酶（MK；由基因MVK编码）活性降低，甲羟戊酸激酶是类异戊二烯生物合成的关键酶。对患者的MVK cDNA进行序列分析，确定了3种不同的突变，其中一种突变在所有患者中都存在。在大肠杆菌中表达突变cDNA表明，所有3种突变均影响所编码蛋白质的活性。此外，免疫印迹分析显示患者成纤维细胞中MK蛋白缺乏，表明这些突变具有使蛋白质不稳定的作用。
