PMID- 10582612
OWN - NLM
STAT- MEDLINE
DCOM- 19991227
LR  - 20190630
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 73
IP  - 6
DP  - 1999 Dec
TI  - Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase
      I: relationship to etiology of dopa-responsive dystonia.
PG  - 2510-6
AB  - 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.
FAU - Suzuki, T
AU  - Suzuki T
AD  - Division of Molecular Genetics, Institute for Comprehensive Medical Science,
      Fujita Health University, Aichi, Japan.
FAU - Ohye, T
AU  - Ohye T
FAU - Inagaki, H
AU  - Inagaki H
FAU - Nagatsu, T
AU  - Nagatsu T
FAU - Ichinose, H
AU  - Ichinose H
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Recombinant Fusion Proteins)
RN  - 22150-76-1 (Biopterin)
RN  - 47E5O17Y3R (Phenylalanine)
RN  - EC 3.5.4.16 (GTP Cyclohydrolase)
RN  - EGX657432I (sapropterin)
SB  - IM
MH  - Amino Acid Sequence
MH  - Biopterin/analogs & derivatives/metabolism
MH  - DNA Mutational Analysis
MH  - Dystonic Disorders/enzymology/*genetics
MH  - Frameshift Mutation
MH  - GTP Cyclohydrolase/deficiency/*genetics/metabolism
MH  - Gene Expression Regulation
MH  - Genes, Dominant
MH  - Genes, Recessive
MH  - Humans
MH  - Molecular Sequence Data
MH  - Neuroblastoma/pathology
MH  - Phenylalanine/blood
MH  - Point Mutation
MH  - Recombinant Fusion Proteins/metabolism
MH  - Tumor Cells, Cultured
EDAT- 1999/12/03 00:00
MHDA- 1999/12/03 00:01
CRDT- 1999/12/03 00:00
PHST- 1999/12/03 00:00 [pubmed]
PHST- 1999/12/03 00:01 [medline]
PHST- 1999/12/03 00:00 [entrez]
AID - 10.1046/j.1471-4159.1999.0732510.x [doi]
PST - ppublish
SO  - J Neurochem. 1999 Dec;73(6):2510-6. doi: 10.1046/j.1471-4159.1999.0732510.x.