Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase I: Relationship to etiology of dopa-responsive dystonia

Takahiro Suzuki, Tamae Oe, Hidehito Inagaki, Toshiharu Nagatsu, Hiroshi Ichinose

研究成果: Article

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To explore the molecular etiology of two disorders caused by a defect in GTP cyclohydrolase I - hereditary progressive dystonia with marked diurnal fluctuation (HPD), also known as dopa-responsive dystonia (DRD), and autosomal recessive GTP cyclohydrolase I deficiency - we purified and analyzed recombinant human wild-type and mutant GTP cyclohydrolase I proteins expressed in Escherichia coli. Mutant proteins showed very low enzyme activities, and some mutants were eluted at a delayed volume on gel filtration compared with the recombinant wild-type. Next, we examined the GTP cyclohydrolase I protein amount by western blot analysis in phytohemagglutinin-stimulated mononuclear blood cells from HPD/DRD patients. We found a great reduction in the amount of the enzyme protein not only in one patient who had a frameshift mutation, but also in an HPD/DRD patient who had a missense mutation. These results suggest that a dominant-negative effect of chimeric protein composed of wild-type and mutant subunits is unlikely as a cause of the reduced enzyme activity in HPD/DRD patients. We suggest that reduction of the amount of the enzyme protein, which is independent of the mutation type, could be a reason for the dominant inheritance in HPD/DRD.

元の言語English
ページ(範囲)2510-2516
ページ数7
ジャーナルJournal of Neurochemistry
73
発行部数6
DOI
出版物ステータスPublished - 29-11-1999

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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