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Dopa‐responsive dystonia is induced by a dominant‐negative mechanism
Author(s) -
Hwu WuhLiang,
Chiou YuWei,
Lai SuYi,
Lee YuMay
Publication year - 2000
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/1531-8249(200010)48:4<609::aid-ana7>3.0.co;2-h
Subject(s) - mutation , dystonia , mutant , biology , penetrance , wild type , protein subunit , allele , mechanism (biology) , genetics , microbiology and biotechnology , medicine , endocrinology , gene , phenotype , neuroscience , philosophy , epistemology
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. Ann Neurol 2000;48:609–613