title: Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation.
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.
authors.affiliation: Department of Medical Genetics and Pediatrics, College of Medicine, National Taiwan University, Taipei, Republic of China.
authors.forename: W L
authors.initials: WL
authors.lastname: Hwu
authors.forename: P J
authors.initials: PJ
authors.lastname: Wang
authors.forename: K J
authors.initials: KJ
authors.lastname: Hsiao
authors.forename: T R
authors.initials: TR
authors.lastname: Wang
authors.forename: Y W
authors.initials: YW
authors.lastname: Chiou
authors.forename: Y M
authors.initials: YM
authors.lastname: Lee
mesh_terms: D019943:Amino Acid Substitution; D002460:Cell Line; D002648:Child; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004274:DNA, Recombinant / Q000235:genetics; D004295:Dihydroxyphenylalanine / Q000627:therapeutic use; D004421:Dystonia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D006136:GTP Cyclohydrolase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005808:Genes, Recessive; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D009154:Mutation; D010957:Plasmids; D017354:Point Mutation; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: D004274:DNA, Recombinant; D012333:RNA, Messenger; D004295:Dihydroxyphenylalanine; D004247:DNA; D006136:GTP Cyclohydrolase