Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome

Houten, Sander M.; Kuis, Wietse; Durán, Marinus; Koning, Tom J. de; Royen‐Kerkhof, Annet van; Romeijn, G. J.; Frenkel, Joost; Dorland, L.; Barse, Martina M.J. de; Huijbers, Wim A. R.; Rijkers, Ger T.; Waterham, Hans R.; Wanders, Ronald J. A.; Poll-Thé, Bwee Tien

doi:10.1038/9691

Cited by 474 publications

(337 citation statements)

References 13 publications

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“…As in other studies (5,21,22), V377I was the most frequent MVK mutation causing HIDS. Furthermore, also in accordance with earlier observations, the majority of patients were compound heterozygous for this genetic defect and another mutation.…”

Section: Discussionsupporting

confidence: 80%

“…At an early step of cholesterol synthesis, it phosphorylates 3,R-mevalonic acid to 5-phosphomevalonate. In HIDS patients, MK activity in cultured skin fibroblasts and lymphocytes is reduced to 1-12% compared with that in controls (4)(5)(6). This leads to a slightly increased urinary excretion of mevalonic acid (Ͻ20 mmoles/mole of creatinine) during a febrile episode.…”

Section: Objective To Describe Biochemical Findings and The Spectrummentioning

confidence: 99%

“…HIDS is caused by mutations in the mevalonate kinase (MVK) gene on chromosome 12q24 which lead to a depressed enzymatic activity of mevalonate kinase (MK) (4,5). MK is a key enzyme of cholesterol and isoprenoid biosynthesis and is present in the cytosol and peroxisomes of every mammalian cell.…”

Section: Objective To Describe Biochemical Findings and The Spectrummentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 80%

Section: Objective To Describe Biochemical Findings and The Spectrummentioning

confidence: 99%

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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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“…The discovery of a gene for FCAS and MWS follows the determination of the genetic basis of several other autoinflammatory syndromes, including the involvement of MVK in hyperIgD syndrome 18,19 and of tumor necrosis factor receptor (TNFR1SF1A) in familial Hibernian fever 20 . Familial Mediterranean fever is caused by mutations in MEFV 15,21 , which encodes a protein called pyrin (also known as marenostirin) that is expressed predominantly in mature neutrophils and is localized to the cytoplasm bound to bundle microtubules [22][23][24] .…”

mentioning

confidence: 99%

Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome

et al. 2001

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Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold [1][2][3][4] . FCAS was previously mapped to a 10-cM region on chromosome 1q44 (refs. 5,6). Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present [6][7][8] . To identify the genes for FCAS and MWS, we screened exons in the 1q44 region for mutations by direct sequencing of genomic DNA from affected individuals and controls. This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS. This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain 9-11 , a nucleotide-binding site (NBS, NACHT subfamily 12 ) domain and a leucine-rich repeat (LRR) motif region 13 , suggesting a role in the regulation of inflammation and apoptosis.We previously identified a locus for FCAS on chromosome 1q44 between markers D1S423 and D1S2682 (ref. 5). We developed a physical contig of bacterial artificial chromosomes (BACs) and P1-derived artificial chromosomes and narrowed the critical region to less than 1 Mb using haplotype analysis (data not shown). We used ESTs mapping to this region and The four-generation family with FCAS (family 1; Fig. 1) has an apparent de novo mutation that first appeared in subject 4 on a chromosome inherited from her mother. Only the affected members of subsequent generations of the family (subjects 5, 9 and 11) inherited this chromosome. We found a missense mutation in subject 4 that segregated with the disease haplotype in subsequent generations (subjects 5, 9 and 11). This mutation was not present in either of her parents (subjects 1 and 2), even though the unaffected mother (subject 2) possessed the haplotype that segregates with disease in this family.The other two families with FCAS (families 2 and 3) also had different missense mutations in the same exon; these were present in all affected family members (Fig. 2). In the one family studied with affected members with a diagnosis of MWS (family 4), both affected individuals had sensorineural hearing loss (Fig. 2). This family also had a missense mutation in the same exon as the families with FCAS. As in family 1, the phenotype of family 4 resulted from a de novo mutation. The unaffected mother (DNA was not available from the father) in family 4 possessed the haplotype that segregates with the disease in subsequent generations (data not shown), but she did not have the mutation that was found in all of the affected family members. These missense mutations were not found in any unaffected individuals in thes...

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“…[1][2][3] This group of diseases comprises three syndromes associated with mutations in NALP3, a key component of the inflammasome 4 : Muckle-Wells syndrome, familial cold urticaria 5 and chronic infantile neurological cutaneous and articular syndrome/ OMID, 6 as well as other syndromes like hyper-IgD, 7,8 PAPA syndrome, 9 TRAPS 10,11 and familial Mediterranean fever (FMF). 12,13 The latter is a recessively inherited disorder, in which mutations occur in the pyrin gene.…”

mentioning

confidence: 99%

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

et al. 2007

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The autoinflammatory disorders Muckle-Wells syndrome, familial cold urtecaria and chronic infantile neurological cutaneous and articular syndrome are associated with mutations in the NALP3 (Cryopyrin) gene, which is the central platform of the proinflammatory caspase-1 activating complex, named the inflammasome. In patients with another autoinflammatory disorder, familial Mediterranean fever (FMF), mutations in the SPRY domain of the Pyrin protein are frequently found. Recent evidence suggests that Pyrin associates with ASC, an inflammasome component, via its Pyrin domain, thereby halting the inflammatory response. This interaction, however, does not explain the effects of mutations of the SPRY domain found in FMF patients. Here we show that the Pyrin SPRY domain not only interacts with NALP3, but also with caspase-1 and its substrate pro-interleukin(IL)-1b. Whereas a Pyrin knockdown results in increased caspase-1 activation and IL-1b secretion, overexpression of the SPRY domain alone blocks these processes. Thus Pyrin binds to several inflammasome components thereby modulating their activity.

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Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome

Cited by 474 publications

References 13 publications

Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

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