Mevalonic aciduria: an inborn error of cholesterol biosynthesis?

Berger, Rolf M. F.; Smit, G. P. A.; Schierbeek, H; Bijsterveld, K.; Coultre, R. Le

doi:10.1016/0009-8981(85)90195-0

Cited by 75 publications

(38 citation statements)

References 3 publications

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“…To date, 6 inborn defects of cholesterol biosynthesis have been described in humans (reviewed in refs. 25,26), and 3 of the associated conditions have cataracts as complications: mevalonic aciduria (27)(28)(29), Smith-Lemli-Opitz syndrome (30)(31)(32), and X-linked dominant chondroplasia punctata 2 (33,34). The cause of cataracts in these diseases was postulated to be due to the decrease in cholesterol level in the lens.…”

Section: Discussionmentioning

confidence: 99%

Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Mori

Li²,

Abe³

et al. 2006

Journal of Clinical Investigation

103

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The Shumiya cataract rat (SCR) is a hereditary cataractous strain. It is thought that the continuous occurrence of poorly differentiated epithelial cells at the bow area of the lens forms the pathophysiological basis for cataract formation in SCRs. In this study, we attempted to identify the genes associated with cataract formation in SCRs by positional cloning. Genetic linkage analysis revealed the presence of a major cataract locus on chromosome 20 as well as a locus on chromosome 15 that partially suppressed cataract onset. Hypomorphic mutations were identified in genes for lanosterol synthase (Lss) on chromosome 20 and farnesyl diphosphate farnesyl transferase 1 (Fdft1) on chromosome 15, both of which function in the cholesterol biosynthesis pathway. A null mutation for Lss was also identified. Cataract onset was associated with the specific combination of Lss and Fdft1 mutant alleles that decreased cholesterol levels in cataractous lenses to about 57% of normal. Thus, cholesterol insufficiency may underlie the deficient proliferation of lens epithelial cells in SCRs, which results in the loss of homeostatic epithelial cell control of the underlying fiber cells and eventually leads to cataractogenesis. These findings may have some relevance to other types of cataracts, inborn defects of cholesterol synthesis, and the effects of cholesterol-lowering medication.

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Section: Discussionmentioning

confidence: 99%

Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Mori

Li²,

Abe³

et al. 2006

Journal of Clinical Investigation

103

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“…MKD has two phenotypes, known as hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and mevalonic aciduria (MA) (Prieur and Griscelli 1984;van der Meer et al 1984;Berger et al 1985). Both phenotypes are characterized by inflammation with fever accompanied by gastrointestinal complaints, lymphadenopathy, arthralgia, myalgia, skin rash, and mucosal ulcers.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Value of Urinary Mevalonic Acid Excretion in Patients with a Clinical Suspicion of Mevalonate Kinase Deficiency (MKD)

et al. 2015

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Objective: In patients suffering from mevalonate kinase deficiency (MKD), the reduced enzyme activity leads to an accumulation of mevalonic acid which is excreted in the urine. This study aims to evaluate the diagnostic value of urinary mevalonic acid measurement in patients with a clinical suspicion of mevalonate kinase deficiency.Methods: In this single-center, retrospective analysis, all patients in whom both measurement of mevalonic acid and genetic testing had been performed in the preceding 17 years have been included. The presence of two pathogenic MVK mutations or demonstration of decreased enzyme activity was considered to be the gold standard for the diagnosis of MKD.Results: Sixty-one patients were included in this study. Thirteen of them harbored two MVK mutations; twelve of them showed elevated levels of mevalonic acid. Forty-eight patients did not harbor any MVK mutations, yet five of them excreted increased amounts of mevalonic acid. This corresponds to a sensitivity of 92%, a specificity of 90%, a positive predictive value of 71%, and a negative predictive value of 98%. The positive likelihood ratio is 10 and the negative likelihood ratio is 0.09.Conclusion: MKD seems very unlikely in patients with a normal mevalonic acid excretion, but it cannot be excluded completely. Further, a positive urinary mevalonic acid excretion still requires MVK analysis to confirm the diagnosis of MKD. Therefore, detection of urinary mevalonic acid should not be mandatory before genetic testing. However, as long as genetic testing is not widely available and affordable, measurement of urinary mevalonic acid is a fair way to select patients for MVK gene analysis or enzyme assay.

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“…A mutation in the gene coding for mevalonate kinase is presumed to be the cause of the recently discovered genetic disease mevalonic aciduria (4,5). The genetic disease is transmitted as an autosomal recessive trait, and there are six reported cases (6).…”

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confidence: 99%

“…The genetic disease is transmitted as an autosomal recessive trait, and there are six reported cases (6). Subjects with mevalonic aciduria have extremely high levels of mevalonate in their plasma and urine, and cells from these subjects have <10% of the normal levels of mevalonate kinase activity (4)(5)(6). As a first step in identifying the molecular defect causing mevalonic aciduria and to study the regulation of mevalonate kinase activity, we have isolated and characterized a cDNA clone coding for rat mevalonate kinase.…”

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confidence: 99%

Molecular cloning of mevalonate kinase and regulation of its mRNA levels in rat liver.

Tanaka¹,

Lee²,

Schafer³

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Mevalonate kinase [ATP:(R)-mevalonate 5-phosphotransferase, EC 2.7.1.36] may be a regulatory site in the cholesterol biosynthetic pathway, and a mutation in the gene coding for this enzyme is thought to cause the genetic disease mevalonic aciduria. To characterize this enzyme, a rat liver cDNA library was screened with a monospecific antibody, and a 1.7-kilobase cDNA clone coding for mevalonate kinase was isolated. A mutation in the gene coding for mevalonate kinase is presumed to be the cause of the recently discovered genetic disease mevalonic aciduria (4, 5). The genetic disease is transmitted as an autosomal recessive trait, and there are six reported cases (6). Subjects with mevalonic aciduria have extremely high levels of mevalonate in their plasma and urine, and cells from these subjects have <10% of the normal levels of mevalonate kinase activity (4-6). As a first step in identifying the molecular defect causing mevalonic aciduria and to study the regulation of mevalonate kinase activity, we have isolated and characterized a cDNA clone coding for rat mevalonate kinase.* Data are also presented to show that long-term regulation of enzyme activity in rat liver is controlled by changes in the levels of mevalonate kinase mRNA. MATERIALS AND METHODSPreparation of the Antiserum. Monospecific antisera to rat mevalonate kinase was prepared in rabbits by using the purified enzyme (3), and the IgG fraction was collected by affinity chromatography (7).Isolation of a cDNA Clone Coding for Mevalonate Kinase. A Agtll cDNA library (8) derived from mRNA purified from the livers of rats treated with diets containing 5% cholestyramine and 0.1% lovastatin was kindly provided by Peter Edwards (UCLA). Positive clones were identified by immunoscreening (9). To obtain a full-length cDNA clone, the cDNA insert from one of the clones was isolated and radiolabeled by random priming (10) to a specific activity of 109 cpm per Ag ofDNA. The radiolabeled probe was used to screen -2 x 105 recombinants. Plaque hybridization was performed as described (8), after which the filters were washed at 680C with 2 x SSC (1x SSC = 0.15 M NaCI/0.015 M sodium citrate, pH 7) containing 0.1% SDS, followed by washes with 0.lx SSC containing 0.1% SDS. Fifteen cDNA clones were isolated. The cDNA inserts were subcloned into the pGEM-3Z vector (Promega) for restriction enzyme mapping or into M13 vectors for DNA sequencing.DNA Sequencing. The DNA sequence of the cDNA was determined by the dideoxynucleotide chain-termination method (11). Sequencing reactions using the Klenow fragment of DNA polymerase I (New England Biolabs) or the modified T7 DNA polymerase (Sequenase, United States Biochemicals) were performed following the manufacturer's protocol. The DNA and protein sequences were aligned using the Intelligenetics computer program, and the EMBL/ GenBank and PIR data bases were searched for homologies to the DNA sequence and protein sequence of mevalonate kinase.Expression of the Mevalonate Kinase cDNA in Saccharomyces cerevisiae. A 1.3-kilobase...

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Mevalonic aciduria: an inborn error of cholesterol biosynthesis?

Cited by 75 publications

References 3 publications

Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Diagnostic Value of Urinary Mevalonic Acid Excretion in Patients with a Clinical Suspicion of Mevalonate Kinase Deficiency (MKD)

Molecular cloning of mevalonate kinase and regulation of its mRNA levels in rat liver.

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