Disease relevance of MVK

• Here, we report on insertional activation of the mevalonate kinase (MK) gene in the human hepatoma cell line PLC/PRF/5 [1].
• Insertional activation of mevalonate kinase by hepatitis B virus DNA in a human hepatoma cell line [1].
• Mevalonate kinase deficiency should be considered in adult patients with fitting neurologic symptoms, with or without periodic fever attacks [2].
• The pathophysiology of these disorders is not yet understood, but eventually will give insight into the in vivo role of mevalonate kinase and isoprenoid biosynthesis with respect to the acute phase response and fever [3].
• (MVK model) to nested case-control data for lung cancers [4].

High impact information on MVK

• Functional analysis demonstrated diminished MK activity in fibroblasts from HIDS patients [5].
• The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts [6].
• The IgD level did not correlate with disease severity, mevalonate kinase enzyme activity, or genotype [7].
• BACKGROUND: The hyper-IgD and periodic fever syndrome (HIDS) is characterized by recurrent attacks of fever, abdominal distress, and arthralgia and is caused by mevalonate kinase mutations [7].
• MEASUREMENTS: Clinical symptoms and signs, immunoglobulin concentration, leukocyte count, erythrocyte sedimentation rate, mutation analysis, and mevalonate kinase enzyme activity assay [7].

Chemical compound and disease context of MVK

• We conclude that mevalonate kinase deficiency leads to a decreased synthesis of ubiquinone-10 and that ubiquinone-10 deficiency is responsible for the clinical progression of this disease characterized by increased lipid peroxidation, cerebellar atrophy, cataract development, and myopathy with increased creatine kinase activity [8].
• Cholesterol biosynthesis, peroxisomes and peroxisomal disorders: mevalonate kinase is not only deficient in Zellweger syndrome but also in rhizomelic chondrodysplasia punctata [9].
• PURPOSE: Mevalonic aciduria in humans results from a genetic deficiency of mevalonate kinase and is characterized by very high plasma mevalonic acid levels, developmental malformations and cataracts [10].

Biological context of MVK

• Patient 1 was heterozygous for a known MVK missense mutation (V377I) and a novel mutation that led to skipping of exon 3 [11].
• CONCLUSION: The genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS [12].
• In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation [12].
• Analysis of the distribution of the V377I allele within patients carrying MVK mutations revealed that this was not according to the Hardy-Weinberg equilibrium principle, most probably due to an under-representation of V377I homozygotes in HIDS [13].
• Based on the V377I allele frequency of 42% in patients diagnosed with MK deficiency, the carrier frequency of any MVK mutation in the Dutch population can be calculated as 1 : 65 [13].

Anatomical context of MVK

• Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured [12].
• Accordingly, when HIDS cell lines were cultured at 39 degrees C, MK activity decreased further [14].
• Specifically, peroxisomes contain at least two enzymes necessary for the initial steps in cholesterol synthesis, i.e., thiolase and mevalonate kinase [15].
• Abnormalities in bone marrow MK maturation that were detected at the electron microscopic level and that led to lysis of numerous MKs were responsible for thrombocytopenia and were similar in both patients [16].
• Immunoblotting of cell extracts from HL-60/ADR cells or HL-60 cells following treatment with TPA revealed increased levels of a 52-kDa species of similar mass to M-kinase [17].

Associations of MVK with chemical compounds

• 2. We describe a girl with heterozygosity for the common MVK V377I mutation and for a novel T(1132) --> C transition, leading to the exchange of serine (TCC) by proline (CCC) at amino-acid position 378 [18].
• OBJECTIVE: The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM 260920) is caused by recessive mutations in the mevalonate kinase gene (MVK), which encodes an enzyme involved in cholesterol and nonsterol isoprenoid biosynthesis [11].
• Her IgD values varied between normal and slightly increased, and the MK activity was in the low-normal range, while urinary mevalonate concentrations were always normal [12].
• This triggered a compensatory increase in 3-hydroxy-3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting [14].
• Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis [19].

Other interactions of MVK

• In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present [12].
• METHODS: Skin fibroblasts from MK-deficient patients and from controls were cultured for 7 days with either simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or zaragozic acid A, an inhibitor of squalene synthase [20].
• Regulatory adaptation of isoprenoid biosynthesis and the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency [21].
• Among these enzymes, MK, IPPI and FPPS activities in the YM-16638-treated group significantly decreased by 38%, 56% and 30%, respectively, when compared to those from control animals receiving no drug treatment [22].
• Sequencing of polymerase chain reaction-amplified cDNAs from cultured cells of three patients with mevalonate kinase deficiency revealed a G --> A transversion at nucleotide 1000 of the coding region, converting alanine to threonine at position 334 (A334T) [23].

Analytical, diagnostic and therapeutic context of MVK

• Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients [24].
• Molecular cloning of human mevalonate kinase and identification of a missense mutation in the genetic disease mevalonic aciduria [25].
• Purified rat mevalonate kinase antibody recognized the gel-purified LRBP on Western blots performed with one- and two-dimensional SDS-polyacrylamide gels [26].
• Additionally, RT-PCR revealed the presence of mRNAs of two peroxisome-associated enzymes of the cholesterol biosynthetic pathway, mevalonate kinase and farnesyl diphosphate synthase [27].
• Northern blot analysis in human CRL1508T cells revealed that quantities of MK poly A+ RNA increased for cells grown in the presence of lipid-deficient calf serum, and further increased upon addition of 1 microM lovastatin [28].

References