GTP CYCLOHYDROLASE I 基因轉殖小鼠啟動子表現及表現型分析
Date Issued
2001
Date
2001
Author(s)
胡務亮
DOI
892314B002387
Abstract
GTP cyclohydrolase I (GCH) is responsible for the
first step of tetrahydrobiopterin (BH4) biosynthesis.
BH4 is an important molecule, because it is the
cofactor of phenylalanine hydroxylase, tyrosine
hydroxylase, tryptophan hydroxylase and nitric oxide
synthase. GCH gene mutations are associated with
wither malignant phenylketonuria and dopa-responsive
dystonia (DRD). Both of them are responsive to
L-dopa treatment. DRD is mostly dominantly inherited,
and through the dominant-negative mechanism.
In the past years, we have isolated a 13kb DNA
from human genomic library containing the 5’ region
(including part of exon 1) of GCH gene. We have
shown that both a 2.8 and 5kb fragments possessed
promoter activity. We connected the 2.8kb fragment to
LacZ gene. The construct was injected into mouse
fertilized egg. We have screened F0 and F1 for the
LacZ mice, but the gene was not expressed. We
inserted a GCH cDNA containing the G201E DRD
mutation after the 5kb promoter. Both F0 and F1
G201E mice were produced.
The phenotype of the transgenic mice was
checked by Rota-Rod. Several mice were found to
have poor performance on the Rota. These mice may
have decreased GCH activity because of the
expression of the dominant negative GCH gene.
However, the offspring of these mice could not
express stably the same phenotype. Therefore, we can
not make conclusion on the association between motor
defect and the transgene.
When the mice were getting old, some of them
demonstrated behavior problem. They tended to make
purposeless circling movement. This could be a late
onset motor abnormality, and may be associated with
the GCH gene. Some mice were from the same
ancestor. These mice have low fertility power, and
many of their babies died shortly after birth. Further
studies on them are going now.
Subjects
Dopa-responsive dystonia
transgenic mice
Publisher
臺北市：國立臺灣大學醫學院小兒科
Type
report
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