Studies on the genotype-phenotype relation in the hph-1 mouse mutant deficient in guanosine triphosphate (GTP) cyclohydrolase I activity

The guanosine triphosphate (GTP) cyclohydrolase I (GTP-CHI) catalyses the r ate-limiting step in the de novo synthesis of tetrahydrobiopterin, a cofact or of three aromatic amino acid hydroxylases, cine of which is phenytalanin e hydroxylase. The hph-1 mouse mutant deficient in GTP-CHI activity exhibit s hyperphenylalaninemia which peculiarly disappears at 3 weeks of age, thus corresponding to the increase in liver GTP-CHI activity. The present gas c hromatographic-mass spectrometric analysis of the phenylalanine and catecho lamine metabolisms demonstrated the former metabolism to remain disturbed e ven in adult hph-1, which demonstrated a metabolic basis for sensitivity to the phenylalanine challenge in adult hph-1. A Northern blot analysis showe d the hepatic GTP-CW RNA expression in hph-1 at 2, 3 and 4 weeks of age to parallel the peculiar time course of the enzyme activity previously reporte d. No mutation was detected in either the coding region or the 5' flanking region (nt. - 1 to -746) of the GTP-CHI gene of the hph-1. Further molecula r genetic analyses are therefore required to elucidate the mechanism of the peculiar phenotype of hph-1. (C) 2000 Elsevier Science B.V. All rights res erved.