title: Molecular characterization of HPH-1: a mouse mutant deficient in GTP cyclohydrolase I activity.
abstract: 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-gamma 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.
authors.affiliation: GSF-Institut für Klinische Molekularbiologie, München, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gütlich
authors.forename: I
authors.initials: I
authors.lastname: Ziegler
authors.forename: K
authors.initials: K
authors.lastname: Witter
authors.forename: B
authors.initials: B
authors.lastname: Hemmens
authors.forename: L
authors.initials: L
authors.lastname: Hültner
authors.forename: J D
authors.initials: JD
authors.lastname: McDonald
authors.forename: T
authors.initials: T
authors.lastname: Werner
authors.forename: W
authors.initials: W
authors.lastname: Rödl
authors.forename: A
authors.initials: A
authors.lastname: Bacher
mesh_terms: D000818:Animals; D001483:Base Sequence; D001708:Biopterins / Q000378:metabolism; D015152:Blotting, Northern; D001853:Bone Marrow; D015815:Cell Adhesion Molecules / Q000494:pharmacology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003208:Concanavalin A / Q000494:pharmacology; D017931:DNA Primers; D004790:Enzyme Induction; D006136:GTP Cyclohydrolase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016366:Open Reading Frames; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D013154:Spleen / Q000378:metabolism; D019089:Stem Cell Factor; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology
chemical_list: D015815:Cell Adhesion Molecules; D017931:DNA Primers; D016298:Hematopoietic Cell Growth Factors; D012333:RNA, Messenger; D019089:Stem Cell Factor; D003208:Concanavalin A; D001708:Biopterins; D007371:Interferon-gamma; D006136:GTP Cyclohydrolase