title: Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome.
abstract: Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is an autosomal recessive inflammatory disorder characterised by recurrent episode of fever associated with lymphadenopathy, abdominal distress, joint involvement and skin lesions. We recently demonstrated that mutations in the mevalonate kinase gene (MVK) are associated with HIDS. Direct DNA sequencing was done to screen the entire coding region of MVK in 25 unrelated patients with HIDS. Mutations were detected in the coding region of the gene including 11 missense mutations, one deletion, the absence of expression of one allele, as well as three novel polymorphisms. Seven of these mutations are novel. The large majority of the patients were compound heterozygotes for two mutations. Of these, V377I (G-->A) is the most common mutation occurring in 20 unrelated patients and was found to be associated with I268T in six patients. Mutations were associated with a decrease of mevalonate kinase (MK) (ATP:mevalonate 5-phosphotransferase, EC 2.7.I.36) enzymatic activity but not as profound as in mevalonic aciduria, a syndrome also caused by a deficient activity of MK. In HIDS the mutations are located all along the protein which is different from mevalonic aciduria where MK mutations are mainly clustered to a same region of the protein. On the basis of this study, we propose that the diagnostic screen of MVK in HIDS should be first directed on V377I and I268T mutations. Three patients are also described to illustrate the genotypic and phenotypic overlap with mevalonic aciduria.
authors: Génétique et physiopathologie des maladies inflammatoires héréditaires, Institut Cochin de Génétique Moléculaire and Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: L
authors: L
authors: Cuisset
authors: J P
authors: JP
authors: Drenth
authors: A
authors: A
authors: Simon
authors: M F
authors: MF
authors: Vincent
authors: S
authors: S
authors: van der Velde Visser
authors: J W
authors: JW
authors: van der Meer
authors: G
authors: G
authors: Grateau
authors: M
authors: M
authors: Delpech
mesh_terms: D000328:Adult; D000483:Alleles; D010505:Familial Mediterranean Fever / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007072:Immunoglobulin D / Q000097:blood*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D017384:Sequence Deletion
chemical_list: D007072:Immunoglobulin D; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase