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Sander M. Houten - One of the best experts on this subject based on the ideXlab platform.
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manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency
Arthritis & Rheumatism, 2006Co-Authors: Marit S Schneiders, Sander M. Houten, Ronald J A Wanders, Marjolein Turkenburg, Hans R. WaterhamAbstract:Objective In cells from patients with the autoinflammatory disorder mevalonate kinase (MK) deficiency, which includes the hyperimmunoglobulin D with Periodic Fever Syndrome, MK becomes the rate-limiting enzyme in the isoprenoid biosynthesis pathway. This suggests that up-regulation of residual MK activity in these patients could be a way in which to prevent or alleviate the associated symptoms. We studied the effect of 2 specific inhibitors of isoprenoid biosynthetic enzymes on the residual activity of MK in cells from patients with MK deficiency. 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. Following culture, MK activity, MK protein levels, MVK messenger RNA levels, and the effect on the pathway flux toward nonsterol isoprenoid biosynthesis were determined. Results Treatment of the fibroblasts with either of the inhibitors led to a marked increase in residual MK enzyme activity, which was largely attributable to increased MVK gene transcription. This effect was even more pronounced when the cells were cultured in lipoprotein-depleted medium. The flux toward nonsterol isoprenoid end-product synthesis was reduced when cells were treated with simvastatin but was partly restored by concomitant treatment with zaragozic acid A. Conclusion Our results indicate that manipulations of the isoprenoid biosynthesis pathway that promote the synthesis of nonsterol isoprenoids may provide an interesting therapeutic option for the treatment of MK deficiency.
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Isoprenoid biosynthesis in hereditary Periodic Fever Syndromes and inflammation.
Cellular and Molecular Life Sciences, 2003Co-Authors: Sander M. Houten, Joost FrenkelAbstract:Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited autoinflammatory disorders mevalonic aciduria and hyperimmunoglobulinemia D and Periodic Fever Syndrome. Since the discovery of the genetic defect, considerable progress has been made in understanding the molecular, biochemical and immunological basis of MK deficiency. Important questions such as which specific protein(s) and/or signaling pathway(s) are affected, however, remain unanswered. Resolving the complete pathophysiology of this disorder is a major challenge, but eventually will give insight into the in vivo role of MK and isoprenoid biosynthesis in inflammation and Fever. This may open novel options for antiinflammatory therapies in general. Here, we give a general introduction on isoprenoid biosynthesis, the regulation thereof and deficiencies therein. We review the molecular, biochemical and immunological aspects of MK deficiency and discuss the relations between isoprenoid biosynthesis and inflammation. Finally, we compare MK deficiency with other autoinflammatory Syndromes.
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carrier frequency of the v377i 1129g a mvk mutation associated with hyper igd and Periodic Fever Syndrome in the netherlands
European Journal of Human Genetics, 2003Co-Authors: Sander M. Houten, Christiaan S Van Woerden, Frits A Wijburg, Ronald J A Wanders, Hans R. WaterhamAbstract:Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and Periodic Fever Syndrome, in the Netherlands
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carrier frequency of the v377i 1129g a mvk mutation associated with hyper igd and Periodic Fever Syndrome in the netherlands
European Journal of Human Genetics, 2003Co-Authors: Sander M. Houten, Christiaan S Van Woerden, Frits A Wijburg, Ronald J A Wanders, Hans R. WaterhamAbstract: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 (1129G>A), 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 between1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis ofpatients 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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temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper igd and Periodic Fever Syndrome
Human Molecular Genetics, 2002Co-Authors: Sander M. Houten, Joost Frenkel, Wietse Kuis, Ger T. Rijkers, Ronald J A Wanders, Hans R. WaterhamAbstract:Hyper-IgD and Periodic Fever Syndrome (HIDS) and mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of Fever and generalized inflammation. Both Syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 � C as compared to 37 � C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 � C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy- 3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and Fever.
Joost Frenkel - One of the best experts on this subject based on the ideXlab platform.
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Mevalonate Kinase Deficiency
2019Co-Authors: Joost FrenkelAbstract:Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease caused by loss of function mutations in both alleles of MVK, the gene encoding the enzyme mevalonate kinase. Deficiency of this enzyme results in impaired isoprenoid biosynthesis. The inflammatory attacks in MKD are characterized by Fever, lymphadenopathy, gastrointestinal symptoms, aphthous ulcers, rash, arthralgias and/or arthritis. Severely affected patients may in addition have neurological involvement, cataract, uveitis, and failure to thrive, often dying in early childhood. This severe end of the phenotypic spectrum is called mevalonic aciduria (MA) as opposed to the milder phenotype also known as hyperimmunoglobulinemia D Periodic Fever Syndrome (HIDS). In this chapter, we detail clinical phenotype and pathophysiological background as well as treatment options.
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Isoprenoid biosynthesis in hereditary Periodic Fever Syndromes and inflammation.
Cellular and Molecular Life Sciences, 2003Co-Authors: Sander M. Houten, Joost FrenkelAbstract:Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited autoinflammatory disorders mevalonic aciduria and hyperimmunoglobulinemia D and Periodic Fever Syndrome. Since the discovery of the genetic defect, considerable progress has been made in understanding the molecular, biochemical and immunological basis of MK deficiency. Important questions such as which specific protein(s) and/or signaling pathway(s) are affected, however, remain unanswered. Resolving the complete pathophysiology of this disorder is a major challenge, but eventually will give insight into the in vivo role of MK and isoprenoid biosynthesis in inflammation and Fever. This may open novel options for antiinflammatory therapies in general. Here, we give a general introduction on isoprenoid biosynthesis, the regulation thereof and deficiencies therein. We review the molecular, biochemical and immunological aspects of MK deficiency and discuss the relations between isoprenoid biosynthesis and inflammation. Finally, we compare MK deficiency with other autoinflammatory Syndromes.
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temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper igd and Periodic Fever Syndrome
Human Molecular Genetics, 2002Co-Authors: Sander M. Houten, Joost Frenkel, Wietse Kuis, Ger T. Rijkers, Ronald J A Wanders, Hans R. WaterhamAbstract:Hyper-IgD and Periodic Fever Syndrome (HIDS) and mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of Fever and generalized inflammation. Both Syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 � C as compared to 37 � C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 � C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy- 3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and Fever.
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Hyper IgD Syndrome (HIDS) associated with in vitro evidence of defective monocyte TNFRSF1A shedding and partial response to TNF receptor blockade with etanercept.
Clinical and experimental immunology, 2002Co-Authors: Peter D. Arkwright, Joost Frenkel, Michael F Mcdermott, Sander M. Houten, Hans R. Waterham, Ebun Aganna, L. J. Hammond, Rita Mirakian, P. I. Tomlin, P. I. VijayduraiAbstract:Hereditary Periodic Fever Syndromes comprise a group of distinct disease entities linked by the defining feature of recurrent febrile episodes. Hyper IgD with Periodic Fever Syndrome (HIDS) is caused by mutations in the mevalonate kinase (MVK) gene. The mechanisms by which defects in the MVK gene cause febrile episodes are unclear and there is no uniformly effective treatment. Mutations of the TNFRSF1A gene may also cause Periodic Fever Syndrome (TRAPS). Treatment with the TNFR-Fc fusion protein, etanercept, is effective in some patients with TRAPS, but its clinical usefulness in HIDS has not been reported. We describe a 3-year-old boy in whom genetic screening revealed a rare combination of two MVK mutations producing clinical HIDS as well as a TNFRSF1A P46L variant present in about 1% of the population. In vitro functional assays demonstrated reduced receptor shedding in proband's monocytes. The proband therefore appears to have a novel clinical entity combining Hyper IgD Syndrome with defective TNFRSF1A homeostasis, which is partially responsive to etanercept.
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lack of isoprenoid products raises ex vivo interleukin 1β secretion in hyperimmunoglobulinemia d and Periodic Fever Syndrome
Arthritis & Rheumatism, 2002Co-Authors: Joost Frenkel, Sander M. Houten, Hans R. Waterham, Ger T. Rijkers, Ronald J A Wanders, Saskia H L Mandey, Sandra W M Buurman, Wietse KuisAbstract:Objective To investigate whether the increased interleukin-1β (IL-1β) secretion in hyperimmunoglobulinemia D and Periodic Fever Syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds. Methods The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 + CD28. Results Lovastatin induced a 15-fold rise in IL-1β secretion by normal anti–CD2 + CD28–stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL-1β secretion. Stimulated MK-deficient cells secreted 9-fold more IL-1β than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1β secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL-1β secretion by these cells. Conclusion In this model, shortage of isoprenoid end products contributes to increased IL-1β secretion by MK-deficient PBMCs, whereas excess mevalonate does not.
Anna Simon - One of the best experts on this subject based on the ideXlab platform.
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tlr2 tlr4 dependent exaggerated cytokine production in hyperimmunoglobulinaemia d and Periodic Fever Syndrome
Rheumatology, 2015Co-Authors: Monique Stoffels, Jos W. M. Van Der Meer, Johanna Jongekrijg, Thijs Remijn, Nina Kok, Anna SimonAbstract:OBJECTIVE: The autoinflammatory hyperimmunoglobulinaemia D and Periodic Fever Syndrome (HIDS) is characterized by recurrent episodes of Fever and inflammation. As part of the mevalonate kinase deficiency spectrum, it is caused by MVK mutations, resulting in decreased mevalonate kinase activity in the isoprenoid pathway. Although IL-1beta is considered a major cytokine in its pathogenesis, IL-1 blockade is not successful in a proportion of patients. We aimed to further characterize the pro-inflammatory cytokine profile of HIDS. METHODS: Peripheral blood mononuclear cells from HIDS patients and healthy donors were incubated with several stimuli. Cytokine concentrations were detected by ELISA. To analyse mRNA and protein expression, we performed quantitative RT-PCR and western blot, respectively. RESULTS: We observed significant differences in cytokine production when cells were incubated with ligands for Toll-like receptor 2 (TLR2), TLR4 and nucleotide-binding oligomerization domain-containing 2 (NOD2). The increased ratio between active and inactive caspase-1 protein in HIDS patients could explain why these cells are more easily triggered to secrete IL-1beta. This is apparently not regulated at the transcriptional level, since expression levels of caspase-1 and IL-1beta mRNA were similar in patients and controls. Both anakinra and tocilizumab treatment resulted in decreased inflammation, both ex vivo as well as in vivo. CONCLUSION: The increased cytokine secretion in HIDS is specific for TLR2, TLR4 and NOD2 ligation. Although IL-1beta is important in the HIDS pathology, our data suggest it is a multicytokine disease. A more rigorous clinical trial is required to determine whether IL-6 receptor blockade may be considered in patients not responding to anakinra treatment.
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Hyper-IgD Syndrome or mevalonate kinase deficiency.
Current opinion in rheumatology, 2011Co-Authors: Monique Stoffels, Anna SimonAbstract:PURPOSE OF REVIEW: The hyper-IgD and Periodic Fever Syndrome (HIDS) is one of the classical monogenetic hereditary autoinflammatory disorders, and together with the more severe mevalonic aciduria it is also known as 'mevalonate kinase deficiency' (MKD). In this study, we will give an overview of the primary research on mevalonate kinase deficiency published in the past 2 years. RECENT FINDINGS: Besides an inventory of a number of recent case reports, literature review shows there are several interesting developments in the basic field of research. First, a group of articles was recently published on chemically instead of genetically induced MKD mouse and cell models, investigating the effects of several isoprenoid pathway intermediates. Second, another study confirms a role for small GTPases and their isoprenylation in the inflammatory response in mevalonate kinase deficiency. Lastly, there are now, finally, modest new indications about the role of IgD. SUMMARY: Both pathophysiological studies and clinical observations in the last 2 years have supported the central role of IL-1 in HIDS. There are some intriguing results and hypotheses about the link between isoprenoid metabolism and the IL-1 pathway through geranylgeranylation that deserve to be further examined.
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concerted action of wild type and mutant tnf receptors enhances inflammation in tnf receptor 1 associated Periodic Fever Syndrome
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Anna Simon, Adrian A Lobito, Adrianna J Jackson, Heiyoung Park, Ravikanth Maddipati, Ariel C Bulua, Jae Jin Chae, Rachel Ettinger, Heleen D De Koning, Anthony CruzAbstract:TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated Periodic Syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of Fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPS-associated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade.
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Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and Periodic Fever Syndrome
Blood, 2006Co-Authors: Evelien J. Bodar, Joost P H Drenth, Jos W. M. Van Der Meer, Jeroen Van Der Hilst, Waander L. Van Heerde, Anna SimonAbstract:Hereditary Periodic Fever Syndromes are characterized by incapacitating attacks of Fever and generalized inflammation. While the mutated genes for the major Syndromes in this group are known, the pathogenesis remains unclear. The aim of this study was to investigate apoptosis in patients with Periodic Fever as a possible pathogenic factor. We measured anisomycin-induced apoptosis with annexin-V flow cytometry and caspase-3/7 activity in peripheral-blood lymphocytes from symptom-free patients with hyper-IgD and Periodic Fever Syndrome (HIDS; n = 10), TNF-receptor-associated Periodic Syndrome (TRAPS; n = 7), and familial Mediterranean Fever (FMF; n = 2). HIDS lymphocytes showed a decreased percentage of apoptosis during remission by both methods compared with controls (17.8% vs 55.4%), whereas no difference was observed in TRAPS or FMF lymphocytes. This defective apoptosis of lymphocytes may be a central pathogenic mechanism in HIDS, since dysfunction of one of the inhibitory mechanisms to curtail the immunologic response could cause an unbridled generalized inflammation after a trivial stimulus.
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effect of etanercept and anakinra on inflammatory attacks in the hyper igd Syndrome introducing a vaccination provocation model
Netherlands Journal of Medicine, 2005Co-Authors: Evelien J. Bodar, J.p.h. Drenth, J.w.m. Van Der Meer, Jeroen Van Der Hilst, Anna SimonAbstract:BACKGROUND: Hyper-IgD and Periodic Fever Syndrome (HIDS) is an hereditary autoinflammatory Syndrome, characterised by recurrent inflammatory attacks. Treatment of HIDS is difficult, although simvastatin is beneficial and etanercept might be effective. Studying the treatment of a rare Periodic Syndrome is complicated by the varying frequency and severity of symptoms and low prevalence. Our aim was to develop a system of clinical observations to evaluate effectiveness of treatment-on-demand. METHODS: Seven Fever episodes in three HIDS patients were monitored, with and without administration of etanercept or anakinra. We developed a clinical score, which includes 12 symptoms. In one patient, inflammatory attacks were provoked by vaccination. RESULTS AND CONCLUSIONS: At the onset of an attack, all patients reported a clinical score between 20 and 25. The score was used to quantify severity and define the end of an attack. Reproducible monitoring of inflammatory episodes was difficult, even in this pilot study. The effect of early administration of etanercept was variable. In one patient, a Fever episode could be readily provoked within 12 to 24 hours by vaccination. In this patient, the IL-1ra analogue anakinra was more successful in aborting the inflammatory attack than etanercept. We propose that this vaccination model will allow evaluation of treatment-on-demand in a controlled setting.
Hans R. Waterham - One of the best experts on this subject based on the ideXlab platform.
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homozygosity for the v377i mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia d and Periodic Fever Syndrome hids
RMD Open, 2016Co-Authors: Laurent Messer, Hans R. Waterham, Ghada Alsaleh, Philippe Georgel, Raphael Carapito, Nassim Daliyoucef, Siamak Bahram, Jean SibiliaAbstract:Objective Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of Fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and Periodic Fever Syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MV K gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. Methods Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. Results Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. Conclusions Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis.
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novel mutations causing hyperimmunoglobulin d and Periodic Fever Syndrome
Indian Pediatrics, 2012Co-Authors: Aditi Sinha, Hans R. Waterham, Vijesh K Sreedhar, Vandana JainAbstract:Hyperimmunoglobulin D and Periodic Fever Syndrome (HIDS) is a rare, hereditary autoinflammatory condition characterized by recurrent inflammatory episodes. We report a 9-year-old boy, diagnosed with HIDS due to two novel mutations, c.62C>T (p.Ala21Val) and c.372-6T>C (probable splicing defect), in the mevalonate kinase (MVK) gene. The pathogenicity of these mutations was confirmed by measurement of low MVK enzyme activity in cultured primary skin fibroblasts of the patient. The symptoms have been refractory to therapy with steroids and non steroidal anti inflammatory drugs. This report expands the genetic and ethnic spectrum of HIDS.
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manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency
Arthritis & Rheumatism, 2006Co-Authors: Marit S Schneiders, Sander M. Houten, Ronald J A Wanders, Marjolein Turkenburg, Hans R. WaterhamAbstract:Objective In cells from patients with the autoinflammatory disorder mevalonate kinase (MK) deficiency, which includes the hyperimmunoglobulin D with Periodic Fever Syndrome, MK becomes the rate-limiting enzyme in the isoprenoid biosynthesis pathway. This suggests that up-regulation of residual MK activity in these patients could be a way in which to prevent or alleviate the associated symptoms. We studied the effect of 2 specific inhibitors of isoprenoid biosynthetic enzymes on the residual activity of MK in cells from patients with MK deficiency. 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. Following culture, MK activity, MK protein levels, MVK messenger RNA levels, and the effect on the pathway flux toward nonsterol isoprenoid biosynthesis were determined. Results Treatment of the fibroblasts with either of the inhibitors led to a marked increase in residual MK enzyme activity, which was largely attributable to increased MVK gene transcription. This effect was even more pronounced when the cells were cultured in lipoprotein-depleted medium. The flux toward nonsterol isoprenoid end-product synthesis was reduced when cells were treated with simvastatin but was partly restored by concomitant treatment with zaragozic acid A. Conclusion Our results indicate that manipulations of the isoprenoid biosynthesis pathway that promote the synthesis of nonsterol isoprenoids may provide an interesting therapeutic option for the treatment of MK deficiency.
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carrier frequency of the v377i 1129g a mvk mutation associated with hyper igd and Periodic Fever Syndrome in the netherlands
European Journal of Human Genetics, 2003Co-Authors: Sander M. Houten, Christiaan S Van Woerden, Frits A Wijburg, Ronald J A Wanders, Hans R. WaterhamAbstract:Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and Periodic Fever Syndrome, in the Netherlands
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carrier frequency of the v377i 1129g a mvk mutation associated with hyper igd and Periodic Fever Syndrome in the netherlands
European Journal of Human Genetics, 2003Co-Authors: Sander M. Houten, Christiaan S Van Woerden, Frits A Wijburg, Ronald J A Wanders, Hans R. WaterhamAbstract: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 (1129G>A), 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 between1 in 5196 and 1 in 53 656, which is far more than actually observed. Although under-diagnosis ofpatients 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.
Wietse Kuis - One of the best experts on this subject based on the ideXlab platform.
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temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper igd and Periodic Fever Syndrome
Human Molecular Genetics, 2002Co-Authors: Sander M. Houten, Joost Frenkel, Wietse Kuis, Ger T. Rijkers, Ronald J A Wanders, Hans R. WaterhamAbstract:Hyper-IgD and Periodic Fever Syndrome (HIDS) and mevalonic aciduria are autosomal recessive disorders characterized by recurrent episodes of Fever and generalized inflammation. Both Syndromes are caused by specific mutations in the gene encoding mevalonate kinase (MK), resulting in a depressed enzymatic activity mainly due to reduced protein levels. We studied the effect of temperature on the activity of wild-type and several mutant MKs in fibroblasts. All fibroblast cell lines from HIDS patients and harbouring the common V377I MVK allele displayed substantially higher MK activities at 30 � C as compared to 37 � C. As shown by temperature inactivation experiments this resulted in a protein nearly as stable as in control cell lines, indicating that primarily the maturation of the protein is affected. Accordingly, when HIDS cell lines were cultured at 39 � C, MK activity decreased further. This triggered a compensatory increase in 3-hydroxy- 3-methylglutaryl-CoA reductase activity, indicating that MK becomes progressively rate-limiting. A similar phenomenon occurs in vivo. MK activity in peripheral blood mononuclear cells drops 2-8-fold when HIDS patients experience febrile attacks. Our results suggest that minor elevations in temperature can set off a chain of events with MK becoming progressively rate-limiting, leading to a temporary deficiency of isoprenoid end-products, which induces inflammation and Fever.
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lack of isoprenoid products raises ex vivo interleukin 1β secretion in hyperimmunoglobulinemia d and Periodic Fever Syndrome
Arthritis & Rheumatism, 2002Co-Authors: Joost Frenkel, Sander M. Houten, Hans R. Waterham, Ger T. Rijkers, Ronald J A Wanders, Saskia H L Mandey, Sandra W M Buurman, Wietse KuisAbstract:Objective To investigate whether the increased interleukin-1β (IL-1β) secretion in hyperimmunoglobulinemia D and Periodic Fever Syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds. Methods The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 + CD28. Results Lovastatin induced a 15-fold rise in IL-1β secretion by normal anti–CD2 + CD28–stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL-1β secretion. Stimulated MK-deficient cells secreted 9-fold more IL-1β than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1β secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL-1β secretion by these cells. Conclusion In this model, shortage of isoprenoid end products contributes to increased IL-1β secretion by MK-deficient PBMCs, whereas excess mevalonate does not.
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lack of isoprenoid products raises ex vivo interleukin 1beta secretion in hyperimmunoglobulinemia d and Periodic Fever Syndrome
Arthritis & Rheumatism, 2002Co-Authors: Joost Frenkel, Sander M. Houten, Hans R. Waterham, Ger T. Rijkers, Ronald J A Wanders, Saskia H L Mandey, Sandra W M Buurman, Wietse KuisAbstract:Objective To investigate whether the increased interleukin-1β (IL-1β) secretion in hyperimmunoglobulinemia D and Periodic Fever Syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds. Methods The effects of lovastatin and farnesol (FOH), geranylgeraniol (GGOH), and mevalonate on peripheral blood mononuclear cells (PBMCs) from 8 patients with MK deficiency and from 13 controls were studied. Lovastatin inhibits isoprenoid biosynthesis by reducing the production of mevalonate. FOH and GGOH restore isoprenoid biosynthesis downstream from MK. Culture supernatants were collected for cytokine analysis 48 hours after stimulation with monoclonal antibodies against CD2 + CD28. Results Lovastatin induced a 15-fold rise in IL-1β secretion by normal anti–CD2 + CD28–stimulated cells (P < 0.001). This effect could be countered by mevalonate and, to a lesser extent, by FOH and GGOH. In the absence of lovastatin, mevalonate did not change IL-1β secretion. Stimulated MK-deficient cells secreted 9-fold more IL-1β than control PBMCs (P < 0.005), rising 2.4-fold in the presence of lovastatin. The effect of lovastatin on IL-1β secretion was reduced by mevalonate, FOH, and GGOH. Isoprenoid biosynthesis in PBMCs from patients was impaired due to the endogenous MK deficiency. Bypassing this defect with FOH, in the absence of lovastatin, led to a 62% reduction (P < 0.02) in IL-1β secretion by these cells. Conclusion In this model, shortage of isoprenoid end products contributes to increased IL-1β secretion by MK-deficient PBMCs, whereas excess mevalonate does not.
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organization of the mevalonate kinase mvk gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia d and Periodic Fever Syndrome
European Journal of Human Genetics, 2001Co-Authors: Sander M. Houten, Janet Koster, Joost Frenkel, Wietse Kuis, G J Romeijn, Richard I. Kelley, U Caruso, Pierre Landrieu, Maja Di Rocco, Bwee Tien PolltheAbstract:Organization of the mevalonate kinase ( MVK ) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and Periodic Fever Syndrome
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organization of the mevalonate kinase mvk gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia d and Periodic Fever Syndrome
European Journal of Human Genetics, 2001Co-Authors: Sander M. Houten, Janet Koster, Joost Frenkel, Wietse Kuis, G J Romeijn, Richard I. Kelley, U Caruso, Pierre Landrieu, Maja Di Rocco, Bwee Tien PolltheAbstract:Mevalonic aciduria (MA) and hyperimmunoglobulinaemia D and Periodic Fever Syndrome (HIDS) are two autosomal recessive inherited disorders both caused by a deficient activity of the enzyme mevalonate kinase (MK) resulting from mutations in the encoding MVK gene. Thus far, disease-causing mutations only could be detected by analysis of MVK cDNA. We now describe the genomic organization of the human MVK gene. It is 22 kb long and contains 11 exons of 46 to 837 bp and 10 introns of 379 bp to 4.2 kb. Three intron-exon boundaries were confirmed from natural splice variants, indicating the occurrence of exon skipping. Sequence analysis of 27 HIDS and MA patients confirmed all previously reported genotypes based on cDNA analysis and identified six novel nucleotide substitutions resulting in missense or nonsense mutations, providing new insights in the genotype/phenotype relation between HIDS and MA.