Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation

GTP cyclohydrolase r (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 (R249 S, 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 R249 S mutant protein possessed normal enzyme activity and kinetics. However, in transfected eukaryotic cells, R249 S 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.