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.
Knappskog
P M
PM
Department of Biochemistry and Molecular Biology, University of Bergen, Norway.
Flatmark
T
T
Mallet
J
J
Lüdecke
B
B
Bartholomé
K
K
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