Molecular characterization of HPH-1: a mouse mutant deficient in GTP cyclohydrolase I activity
McDonald, J. David
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Gutlich, M.; Ziegler, I.; Witter, K.; Hemmens, B.; Hultner, L.; Mcdonald, J. David; Werner, T.; Rodl, W.; Bacher, A. 1994. Molecular Characterization of HPH-1: A Mouse Mutant Deficient in GTP Cyclohydrolase I Activity. Biochemical and Biophysical Research Communications, v.203 no. 3 pp.1675-1681
GTP cyclohydrolase I catalyzes the initial and rate limiting step of the biosynthesis of tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylation. The mouse mutant HPH-1, previously generated by chemical mutagenesis, shows a phenylketonuria due to decreased hepatic GTP cyclohydrolase I activity. We show that both parameters GTP cyclohydrolase I activity and tetrahydrobiopterin synthesis significantly increase after weaning, but remain reduced during the lifetime. In the wild type mouse (C57BL/6), interferon-γ and kit ligand induce GTP cyclohydrolase I activity in primed T-cells and in bone marrow-derived mast cells, respectively. The same is true for the HPH-1 mutant, but the absolute values remain lower throughout. The open reading frame of GTP cyclohydrolase I is not affected by the hph-1 mutation as shown by sequencing. Northern blot analysis demonstrates a marked decrease in the steady state mRNA level specific for GTP cyclohydrolase I.
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