title: Missense mutants inactivate guanosine triphosphate cyclohydrolase I in hereditary progressive dystonia.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Nara Medical University, Shijo-cho 840, Kashihara, 634-8521, Nara, Japan. sueno@nmu-gw.cc.naramed-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Ueno
authors.forename: M
authors.initials: M
authors.lastname: Hirano
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells / Q000201:enzymology; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D006136:GTP Cyclohydrolase