title: Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome.
abstract: 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 degrees C as compared to 37 degrees 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 degrees 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.
authors.affiliation: Departments of Paediatrics/Emma Children's Hospital and Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Joost
authors.initials: J
authors.lastname: Frenkel
authors.forename: Ger T
authors.initials: GT
authors.lastname: Rijkers
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Wietse
authors.initials: W
authors.lastname: Kuis
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D001831:Body Temperature; D002478:Cells, Cultured; D010505:Familial Mediterranean Fever / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D005347:Fibroblasts / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006942:Hypergammaglobulinemia / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D007072:Immunoglobulin D / Q000097:blood*; D007532:Isoleucine / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008798:Mevalonic Acid / Q000097:blood; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012867:Skin / Q000201:enzymology / Q000473:pathology; D014633:Valine / Q000235:genetics
chemical_list: D007072:Immunoglobulin D; D007532:Isoleucine; D006903:Hydroxymethylglutaryl CoA Reductases; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D014633:Valine; D008798:Mevalonic Acid