A novel missense mutant inactivates GTP cyclohydrolase I in dope-responsive dystonia

Dopa-responsive dystonia (DRD) due to mutant GTP cyclohydrolase I (GCH) sho ws the considerable heterogeneity of clinical phenotypic expression. To exp lain the clinical diversity, we studied a Japanese family with a novel muta nt GCH (GCH-G90V), where an affected heterozygote had a higher mutant/norma l mRNA ratio than an unaffected heterozygote. Coexpression experiments usin g the mutant with wild-type GCH showed that GCH-G90V inactivated the normal enzyme in a dose-dependent manner, suggesting that the dominant negative e ffect of a mutant GCH on the normal enzyme might be one of the molecular me chanisms for the clinical heterogeneity of DRD. (C) 1999 Elsevier Science I reland Ltd. All rights reserved.