Hyperphenylalaninemia in the hph-1 Mouse Mutant

Abstract

ABSTRACT. A mutation, resulting in a deficiency of liver GTP-cyclohydrolase activity, has been induced in the laboratory mouse. Mice homozygous for this mutation exhibit hyperphenylalaninemia under the following conditions: 1 ) early in life and 2) throughout life when exposed to phenylalanine. A phenylalanine loading regimen was used to discriminate between mutant and wild type mice on the basis of the resultant phenylalanine and tyrosine serum levels. Subjecting mice to this regimen reveals several distinguishing characteristics. Mutant mice exhibit approximately 2-fold higher peak phenylalanine levels than wild-type mice. In wild-type mice the hyperphenylalaninemic state is transient and rapidly abates while in mutant mice it is persistent and remains for a prolonged period. Mutant mice exhibit normal serum tyrosine levels after a loading challenge, while wild-type mice experience an increase in tyrosine levels. The loading regimen was also used to gauge the response of mutant hyperphenylalaninemic mice to exposure to chemical compounds required for normal phenylalanine catabolism (i.e. pteridine cofactors of the phenylalanine hydroxylase reaction). Mutant mice exposed to native enzyme cofactor or cofactor precursors exhibit a sharp decline in serum phenylalanine levels relative to their uninjected counterparts coupled with a tyrosine increase. By contrast, mutant mice exposed to nonprecursor compounds that are structurally related to the native cofactor, experience no diminution of serum phenylalanine levels. (Pediatr Res 23: 63-67, 1988)

The Roles of Pteridine Reductase 1 and Dihydrofolate Reductase-Thymidylate Synthase in Pteridine Metabolism in the Protozoan Parasite Leishmania major

“…Modulation of antifolate inhibition also has been noted in the malaria parasite Plasmodium falciparum (65). In contrast, mammalian cells show relatively little effect and lack oxidized pteridine reductase activity (51,66). Under conditions where DHFR-TS is inhibited, the ability of PTR1 in wild-type Leishmania to synthesize reduced folates could play a significant role in the modulation of MTX potency.…”

Hepatic gene therapy: adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes.

“…To determine ifthe system could be used to reconstitute enzymatic activities in phenylketonuria, a plasmid containing the hPAH cDNA under the control of the CMV enhancer/promoter was used for complex formation. A PAH-deficient mouse strain has been developed in which the hepatic enzyme level is only 3% of normal (29). Hepatocytes isolated from PAH-deficient mice were incubated with complex made with a ratio of ASOR to DNA of 250:1.…”

sar: a genetic mouse model for human sarcosinemia generated by ethylnitrosourea mutagenesis.

“…When only the phenotype is known, germline mutagenesis followed by backcrossing and phenotypic screening has been successful. The latter approach utilizing ethylnitrosourea (ENU) mutagenesis has been used to develop hyperphenylalaninemic mice strains, deficient in phenylalanine hydroxylase or GTP cyclohydrolase activities (2,3), and muscular dystrophic mice with defective dystrophin (4).…”