Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome.
Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.
Houten
S M
SM
Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, The Netherlands.
Kuis
W
W
Duran
M
M
de Koning
T J
TJ
van Royen-Kerkhof
A
A
Romeijn
G J
GJ
Frenkel
J
J
Dorland
L
L
de Barse
M M
MM
Huijbers
W A
WA
Rijkers
G T
GT
Waterham
H R
HR
Wanders
R J
RJ
Poll-The
B T
BT
D019943:Amino Acid Substitution; D003001:Cloning, Molecular; D004926:Escherichia coli; D005260:Female; D005334:Fever / Q000201:enzymology / Q000235:genetics*; D005808:Genes, Recessive; D006801:Humans; D006942:Hypergammaglobulinemia / Q000201:enzymology / Q000235:genetics*; D007072:Immunoglobulin D; D007214:Indonesia; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008798:Mevalonic Acid / Q000097:blood; D009426:Netherlands; D010507:Periodicity; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics*; D017354:Point Mutation; D011994:Recombinant Proteins / Q000096:biosynthesis; D012008:Recurrence; D013577:Syndrome
D007072:Immunoglobulin D; D011994:Recombinant Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D008798:Mevalonic Acid