MOLECULAR CHARACTERIZATION OF HPH-1 - A MOUSE MUTANT DEFICIENT IN GTPCYCLOHYDROLASE-I ACTIVITY

GTP cyclohydrolase I catalyzes the initial and rate limiting step of t he biosynthesis of tetrahydrobiopterin, the cofactor for aromatic amin o 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 cyclo hydrolase I activity and tetrahydrobiopterin synthesis significantly i ncrease 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 b y sequencing. Northern blot analysis demonstrates a marked decrease in the steady state mRNA level specific for GTP cyclohydrolase I. (C) 19 94 Academic Press, Inc.