TY - JOUR
T1 - Studies on the genotype-phenotype relation in the hph-1 mouse mutant deficient in guanosine triphosphate (GTP) cyclohydrolase I activity
AU - Maeda, Toyoki
AU - Haeno, Shigehiko
AU - Oda, Kazumi
AU - Mori, Daisuke
AU - Ichinose, Hiroshi
AU - Nagatsu, Toshiharu
AU - Suzuki, Tomokazu
PY - 2000/9
Y1 - 2000/9
N2 - The guanosine triphosphate (GTP) cyclohydrolase I (GTP-CHI) catalyses the rate-limiting step in the de novo synthesis of tetrahydrobiopterin, a cofactor of three aromatic amino acid hydroxylases, one of which is phenylalanine hydroxylase. The hph-1 mouse mutant deficient in GTP-CHI activity exhibits hyperphenylalaninemia which peculiarly disappears at 3 weeks of age, thus corresponding to the increase in liver GTP-CHI activity. The present gas chromatographic-mass spectrometric analysis of the phenylalanine and catecholamine metabolisms demonstrated the former metabolism to remain disturbed even in adult hph-1, which demonstrated a metabolic basis for sensitivity to the phenylalanine challenge in adult hph-1. A Northern blot analysis showed the hepatic GTP-CHI RNA expression in hph-1 at 2, 3 and 4 weeks of age to parallel the peculiar time course of the enzyme activity previously reported. 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 molecular genetic analyses are therefore required to elucidate the mechanism of the peculiar phenotype of hph-1. Copyright (C) 2000 Elsevier Science B.V.
AB - The guanosine triphosphate (GTP) cyclohydrolase I (GTP-CHI) catalyses the rate-limiting step in the de novo synthesis of tetrahydrobiopterin, a cofactor of three aromatic amino acid hydroxylases, one of which is phenylalanine hydroxylase. The hph-1 mouse mutant deficient in GTP-CHI activity exhibits hyperphenylalaninemia which peculiarly disappears at 3 weeks of age, thus corresponding to the increase in liver GTP-CHI activity. The present gas chromatographic-mass spectrometric analysis of the phenylalanine and catecholamine metabolisms demonstrated the former metabolism to remain disturbed even in adult hph-1, which demonstrated a metabolic basis for sensitivity to the phenylalanine challenge in adult hph-1. A Northern blot analysis showed the hepatic GTP-CHI RNA expression in hph-1 at 2, 3 and 4 weeks of age to parallel the peculiar time course of the enzyme activity previously reported. 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 molecular genetic analyses are therefore required to elucidate the mechanism of the peculiar phenotype of hph-1. Copyright (C) 2000 Elsevier Science B.V.
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U2 - 10.1016/s0387-7604(00)00133-9
DO - 10.1016/s0387-7604(00)00133-9
M3 - Article
C2 - 10984661
AN - SCOPUS:0033839294
VL - 22
SP - 50
EP - 53
JO - Brain and Development
JF - Brain and Development
SN - 0387-7604
IS - SUPPL. 1
ER -