title: Dopa-responsive dystonia is induced by a dominant-negative mechanism.
abstract: Dopa-responsive dystonia (DRD) is induced by a deficiency of GTP cyclohydrolase I (GCH) and has a postulated autosomal dominant inheritance with a low penetrance. G201E is a dominant DRD mutation. Recombinant G201E mutant protein possessed very low enzyme activity. When G201E was expressed in eukaryotic cells, only a small amount of GCH protein could be detected. In baby hamster kidney cells, G201E protein was synthesized normally but was degraded rapidly in pulse-chase experiments. More interestingly, G201E dramatically decreased the level of wild-type protein and GCH activity in cotransfection studies. Therefore, G201E exerts a dominant-negative effect on the wild-type protein, probably going through an interaction between them. We also showed that L79P but not R249S (a recessive DRD mutation) had a dominant-negative effect. Through the dominant-negative mechanism, a single mutation could decrease GCH activity to less than 50% of normal. This study not only explains the inheritance of DRD but also increases the understanding of genetic diseases associated with multiple subunit proteins.
authors.affiliation: Department of Pediatrics and Medical Genetics, College of Medicine, National Taiwan University, Taipei, Republic of China.
authors.forename: W L
authors.initials: WL
authors.lastname: Hwu
authors.forename: Y W
authors.initials: YW
authors.lastname: Chiou
authors.forename: S Y
authors.initials: SY
authors.lastname: Lai
authors.forename: Y M
authors.initials: YM
authors.lastname: Lee
mesh_terms: D000818:Animals; D006224:Cricetinae; D004295:Dihydroxyphenylalanine / Q000627:therapeutic use*; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics*; D006136:GTP Cyclohydrolase / Q000172:deficiency* / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D009154:Mutation / Q000235:genetics
chemical_list: D004295:Dihydroxyphenylalanine; D006136:GTP Cyclohydrolase