Dopa-responsive dystonia is induced by a dominant-negative mechanism

Dopa-responsive dystonia (DRD) is induced by a deficiency of GTP cyclohydro lase I (GCH) and has a postulated autosomal dominant inheritance with a low penetrance. G201E is a dominant DRD mutation. Recombinant G201E mutant pro tein possessed very low enzyme activity. When G201E was expressed in eukary otic cells, only a small amount of GCH protein could be detected. In baby h amster kidney cells, G201E protein was synthesized normally but was degrade d rapidly in pulse-chase experiments, More interestingly, G201E dramaticall y decreased the level of wild-type protein and GCH activity in cotransfecti on studies. Therefore, G201E exerts a dominant-negative effect on the wild- type protein, probably going through an interaction between them. We also s howed that L79P but not R249S (a recessive DRD mutation) had a dominant-neg ative effect. Through the dominant-negative mechanism, a single mutation co uld decrease GCH activity to less than 50% of normal. This study not only e xplains the inheritance of DRD but also increases the understanding of gene tic diseases associated with multiple subunit proteins.