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 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.
Maeda
T
T
The Department of Clinical Genetics, The Institute of Bioregulation, Kyushu University, Beppu Tsurumihara 4546, 874-0838, Oita, Japan.
Haeno
S
S
Oda
K
K
Mori
D
D
Ichinose
H
H
Nagatsu
T
T
Suzuki
T
T
D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D002395:Catecholamines / Q000652:urine; D006136:GTP Cyclohydrolase / Q000172:deficiency* / Q000235:genetics*; D005838:Genotype; D051379:Mice; D008817:Mice, Mutant Strains / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D010649:Phenylalanine / Q000652:urine; D012333:RNA, Messenger / Q000378:metabolism
D002395:Catecholamines; D012333:RNA, Messenger; D001708:Biopterins; D010649:Phenylalanine; D006136:GTP Cyclohydrolase; C003402:sapropterin