Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene.
Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of dopamine. Recently, we described a point mutation in hTH (Q381K) in a family of two siblings suffering from progressive L-DOPA-responsive dystonia (DRD), representing the first reported mutation in this gene. We here describe the cloning, expression and steady-state kinetic properties of the recombinant mutant enzyme. When expressed by a coupled in vitro transcription-translation system and in E. coli, the mutant enzyme represents a kinetic variant form, with a reduced affinity for L-tyrosine. The 'residual activity' of about 15% of the corresponding wild-type hTH (isoform hTH1), at substrate concentrations prevailing in vivo, is compatible with the clinical phenotype of the two Q381K homozygote patients carrying this recessively inherited mutation.
Department of Biochemistry and Molecular Biology, University of Bergen, Norway.
P M
PM
Knappskog
T
T
Flatmark
J
J
Mallet
B
B
Lüdecke
K
K
Bartholomé
D000818:Animals; D001483:Base Sequence; D003062:Codon; D004421:Dystonia / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
D003062:Codon; D011994:Recombinant Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase