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.