Dopa-Responsive Dystonia Is Induced by a Dominant-Negative Mechanism
Resource
ANNALS OF NEUROLOGY v.48 n.4 pp.609-613
Journal
ANNALS OF NEUROLOGY
Journal Volume
v.48
Journal Issue
n.4
Pages
609-613
Date Issued
2000
Date
2000
Author(s)
HWU, WUH-LIANG
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 G201 E 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.
Type
journal article