Missense mutants inactivate guanosine triphosphate cyclohydrolase I in hereditary progressive dystonia

Hereditary progressive dystonia (HPD) with marked diurnal fluctuation is caused by mutant guanosine triphosphate (GTP) cyclohydrolase I (GCH). The clinical presentation of dominant HPD varies considerably. We proposed the hypothesis that a relative increase of mutant GCH capable of inhibiting normal GCH is responsible for heterogeneous phenotypic manifestations. In a Japanese family with a novel G90V mutation, an affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote. Co-expression analysis showed that mutant enzyme (GCH-G90V) inactivated the normal enzyme in the COS cells. Similarly, GCH-G203R showed the dominant negative effects. These results supported our proposed hypothesis.