Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation
Journal
Human Genetics
Journal Volume
105
Journal Issue
3
Pages
226-230
Date Issued
1999
Author(s)
Abstract
GTP cyclohydrolase I (GTPCH) catalyzes the rate-limiting step of tetrahydrobiopterin (BH4) biosynthesis. GTPCH has been associated with two clinically distinct human diseases: the recessive hyperphenylalaninemia (HPA) and the dominant dopa-responsive dystonia (DRD). We found a recessive GTPCH mutation (R249S, 747C→G) in a dystonia patient. Her PHA-stimulated mononuclear blood cells had a normal amount of GTPCH mRNA, but low GTPCH activity. Arginine 249 is located at the C-terminus of GTPCH, outside the catalytic site. E. coli expressed recombinant R249S mutant protein possessed normal enzyme activity and kinetics. However, in transfected eukaryotic cells, R249S mutant protein expression level was lower than the wild-type protein. Therefore, this is suspected to be a destabilizing mutation. Our data suggest that DRD could be either dominantly or recessively inherited, and the inheritance might be determined by the mechanism of mutation.
Other Subjects
dopa; guanosine triphosphate cyclohydrolase i; messenger RNA; mutant protein; phytohemagglutinin; recombinant enzyme; article; case report; controlled study; dystonia; enzyme active site; enzyme activity; enzyme kinetics; escherichia coli; female; gene mutation; human; human cell; mononuclear cell; priority journal; protein expression; recessive gene; school child; Amino Acid Substitution; Cell Line; Child; Dihydroxyphenylalanine; DNA; DNA Mutational Analysis; DNA, Recombinant; Dystonia; Escherichia coli; Female; Gene Expression Regulation, Enzymologic; Genes, Recessive; GTP Cyclohydrolase; Hela Cells; Homozygote; Humans; Mutation; Plasmids; Point Mutation; RNA, Messenger
Type
journal article