Identification and Characterization of Three Novel Missense Mutations in Mevalonate Kinase cDNA Causing Mevalonic Aciduria, a Disorder of Isoprene Biosynthesis

Romeijn, G. J.; Koster, Janet; Gray, R. G. F.; Darbyshire, P. J.; Smit, G. P. A.; Klerk, J. B. C. de; Durán, Marinus; Gibson, K. Michael; Wanders, Ronald J. A.; Waterham, Hans R.

doi:10.1093/hmg/8.8.1523

Cited by 58 publications

(57 citation statements)

References 26 publications

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“…This suggests that also the combination of A334T and V377I may have a reduced penetrance. In contrast to other mutations which often affect stability of the MK protein, 3,10,16 A334T encodes a stable MK with a decreased affinity for its substrate mevalonate. 24 This mutant MK protein may be able to stabilise the V377I mutant since MK functions as a dimer.…”

Section: Resultsmentioning

confidence: 97%

“…Four of these were heterozygotes for the A334T (1000G4A) allele, and one patient was homozygous for I268T. 10 From these data the proportion 'R' of the V377I allele among Dutch patients with MK deficiency can be calculated as 42% (33 V377I alleles/78 MVK alleles).…”

Section: Resultsmentioning

confidence: 99%

“…7,10 In HIDS, however, a residual MK activity varying between 1 and 7% can be measured both in fibroblasts and leukocytes from patients. 3,10 -12 MK is an essential enzyme in the isoprenoid/cholesterol biosynthesis pathway and converts mevalonate into 5-phosphomevalonate.…”

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confidence: 99%

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Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

et al. 2003

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Hyper-IgD and periodic fever syndrome (HIDS) and mevalonic aciduria (MA) are two autosomal recessive disorders that both are caused by a deficient activity of the enzyme mevalonate kinase (MK) due to mutations in the encoding gene (MVK). The most frequently occurring MVK mutation, V377I (1129G4A), has been identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MA. To estimate the incidence of MK deficiency in the Netherlands, we determined the carrier frequency of the V377I mutation in genomic DNA extracted from anonymised newborn screening cards by PCR-RFLP. We found 14 carriers among 2138 analysed samples (1 : 153). 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. This predicts a disease incidence between 1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis of patients with MK deficiency remains possible, this discrepancy probably is due to a reduced penetrance of V377I homozygosity. 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. Homozygotes for V377I might exhibit a much milder phenotype of MK deficiency or no disease-phenotype at all.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

et al. 2003

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“…Three mutations (A148T, R215Q and I268T) had already been reported in association with the MKD phenotype, 12 while the c.928G4A (V310M) mutation had previously been identified in one MA patient in homozygous state. 20 The remaining eight mutations had never been described previously (Table 3). It is worth noting that three of them, H20Q, G211E and L265R, found in patients #6, #5 and #12, respectively, affect codons which have already been involved in different MKD, both the previously called HIDS and MA, associated nucleotide and amino-acidic changes (H20N or H20P, G211A and L265P).…”

Section: Resultsmentioning

confidence: 99%

MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever

et al. 2004

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Autosomal recessive autoinflammatory disorder caused by mutations of the mevalonate kinase gene (MVK), leading to mild, incomplete MK enzyme deficiency (MKD), has been known so far as Hyper-IgD and periodic fever syndrome (HIDS) and regarded as mostly occurring in Northern Europe. Here we report the results of the molecular characterization of the first Italian series of patients affected with autoinflammatory disorders and periodic fever. A total of 13 different mutations, scattered throughout the MVK coding region, were identified in either homozygous or compound heterozygous state in 15 patients. The mutation leading to the V377I amino-acid change, already described also in other series, resulted the most common with a frequency of 50% of all MKD alleles. Among the other mutations, eight had never been described before, including an interstitial deletion of 19 nucleotides in exon 2. In addition to these nucleotide changes, private and polymorphic MVK variants have been detected in the patients under analysis and checked also in a set of control individuals. Clinical features are reported for each of the 15 MKD patients, and life-threatening infections and systemic amyloidosis presented as unexpected MKDrelated complications. Our study demonstrates that MKD is a common cause of recurrent fever also in the Italian population, where it is associated with both a wide spectrum of previously unreported MVK mutations and peculiar phenotypic features.

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“…251170), and renal excretion of mevalonic acid is much higher (from ϳ3,000 mmoles/mole of creatinine up to Ͼ56,000 mmoles/mole of creatinine). In addition to the typical clinical picture of HIDS, MA patients present with psychomotor retardation, facial dysmorphia, cataract, failure to thrive, and ataxia (6)(7)(8). Thus, MK deficiency comprises a continuous spectrum of loss of enzymatic activity, with the severe phenotype of MA at the most pathologic extreme, occurring in Ͻ1% of MK-deficient patients, and with HIDS as the milder variant.…”

Section: Objective To Describe Biochemical Findings and The Spectrummentioning

confidence: 99%

Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: A low‐penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa

Stojanov¹,

Lohse²,

Lohse³

et al. 2004

Arthritis & Rheumatism

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Objective. To describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A lowpenetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).Methods. The MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. 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. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured.Results. Mutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). 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.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.The hyperimmunoglobulinemia D with periodic fever syndrome (HIDS; MIM no. 260920) is an autosomal recessively inherited autoinflammatory disease. It is characterized by febrile episodes of 3-7 days' duration recurring every 4-8 weeks and by a persistently high serum level of IgD (Ͼ100 IU/ml). Symptoms accompanying a typical attack comprise cervical lymphadeno-

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Identification and Characterization of Three Novel Missense Mutations in Mevalonate Kinase cDNA Causing Mevalonic Aciduria, a Disorder of Isoprene Biosynthesis

Cited by 58 publications

References 26 publications

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands

MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever

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