Disease relevance of hph1

• Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice [1].
• The hph-1 mice have defective tetrahydrobiopterin biosynthesis and share many neurochemical similarities with l-dopa-responsive dystonia (DRD) in humans [2].
• These latter strains have levels of HPH very similar to human PKU patients, exhibit a phenylalanine-dependent hypopigmentation, and have reproductive difficulties that resemble human maternal PKU [3].
• A histological study of the hph-1 mouse mutant: an animal model of phenylketonuria and infantile hypertrophic pyloric stenosis [4].
• Mice lacking HNF1alpha are born normally but suffer from several defects including hyperphenylalaninemia, defective bile acid and cholesterol metabolism, an insulin secretion defect and renal Fanconi syndrome [5].

Psychiatry related information on hph1

• Hyperphenylalaninemia leads to a decrease in neurotransmitter receptor density and, therefore, to a decrease in connectivity, which may form the basis for the mental retardation in this condition [6].

High impact information on hph1

• Treatment from birth with a low phenylalanine diet largely prevents the deviant cognitive phenotype by ameliorating HPA and is recognized as one of the first effective treatments of a genetic disease [7].
• Phenylketonuria (PKU), with its associated hyperphenylalaninemia (HPA) and mental retardation, is a classic genetic disease and the first to have an identified chemical cause of impaired cognitive development [7].
• Mutant mice exhibiting heritable hyperphenylalaninemia have been isolated after ethylnitrosourea mutagenesis of the germ line [8].
• Severe chronic hyperphenylalaninemia can be produced when mutant homozygotes are given phenylalanine in their drinking water [8].
• To investigate the pathophysiology, we have begun to characterize biogenic amine and BH4 metabolism in the GTP cyclohydrolase deficient hph-1 mouse [9].

Chemical compound and disease context of hph1

• BH4-responsive PAH deficiency is a variant of hyperphenylalaninemia or phenylketonuria (PKU) caused by mutations in the human PAH gene that respond to oral BH4 loading by stimulating enzyme activity and therefore lowering serum phenylalanine [10].
• To produce genetic-based animal models for the human disease phenylketonuria (PKU), we treated mice with the powerful germline mutagen ethylnitrosourea and screened the progeny of these animals for the symptom hyperphenylalaninemia (HPH) [3].
• Applying ethionine together with phenylalanine resulted in hyperphenylalaninemia and phenylketonuria [11].
• In the present study, we investigated hyperphenylalaninemia-related brain serotonin depletion using a genetic mouse model of phenylketonuria, the Pah(enu2) mutant [12].
• Measurement of phenyllactate, phenylacetate, and phenylpyruvate by negative ion chemical ionization-gas chromatography/mass spectrometry in brain of mouse genetic models of phenylketonuria and non-phenylketonuria hyperphenylalaninemia [13].

Biological context of hph1

• These results suggest that the hph-1 mutation may involve alteration of the catalytic site but does not detectably alter the whole enzyme structure [14].
• Among 328 different mutations by state (Fig. 2) the majority are rare mutations causing hyperphenylalaninemia (HPA) (OMIM 261600), the remainder are polymorphic variants without apparent effect on phenotype [15].
• Only six different mutations account for 60% of human HPA chromosomes worldwide, mutations stratify by population and geographic region, and the Oriental and Caucasian mutation sets are different (Fig. 3). PAHdb provides curated electronic publication and one third of its incoming reports are direct submissions [15].
• PAHdb modules contain mutations, polymorphic haplotypes, genotype-phenotype correlations, expression analysis, sources of information and the reference sequence; the database also contains pages of clinical information and data on three ENU mouse orthologues of human HPA [15].
• GTP cyclohydrolase I gene expression in the brains of male and female hph-1 mice [16].

Anatomical context of hph1

• We employed hepatocyte transplantation under selective growth conditions to investigate the minimal number of PAH-expressing hepatocytes necessary to prevent hyperphenylalaninemia in mice [17].
• Expression of phenylalanine hydroxylase (PAH) in erythrogenic bone marrow does not correct hyperphenylalaninemia in Pah(enu2) mice [18].
• Previous experiments with liver PAH-deficient transgenic mice that expressed PAH in skeletal muscle demonstrated transient correction of hyperphenylalaninemia only with hourly parenteral BH(4) administration [19].
• Aortas from 8-week-old hph-1 and wild-type mice (C57BLxCBA) were compared [20].
• The inhibition of these processes in the hph-1 mouse ileum suggests that BH4 may be a target for the modulation of electrogenic transport, and highlight the complexity of the interactions between nitric oxide and cyclic GMP in the gut [21].

Associations of hph1 with chemical compounds

• Tetrahydrobiopterin deficiency and brain nitric oxide synthase in the hph1 mouse [22].
• Mice homozygous for this mutation exhibit hyperphenylalaninemia under the following conditions: 1) early in life and 2) throughout life when exposed to phenylalanine [23].
• The hph-1 mouse which displays tetrahydrobiopterin deficiency and impaired dopamine and serotonin turnover, has been used to study cofactor replacement therapy for disorders causing brain tetrahydrobiopterin deficiency [24].
• We found a strong association between the levels of BH4 and cyclic GMP in hph-1 mice but not in wild-type animals [25].
• Neurochemical effects following peripheral administration of tetrahydropterin derivatives to the hph-1 mouse [24].

Regulatory relationships of hph1

• Only in hph-1 mice were the relaxations inhibited by catalase and enhanced by superoxide dismutase [20].
• In contrast, iNOS specific activity and iNOS protein were enhanced in hph-1 stimulated astrocytes by 40 and 60%, respectively when compared with wild type [26].

Other interactions of hph1

• These mice exhibited hyperphenylalaninemia at baseline, but serum phenylalanine levels decreased significantly when the mice were supplemented with tetrahydrobiopterin (BH4), a required cofactor for PAH [27].
• The DPS-rescued (Pts(-/-), DPS) mice showed severe hyperphenylalaninemia [28].
• In addition, demonstration of central monoamine changes in the hph-1 mouse make it a possible model system for the investigation of the neuropathological mechanisms in Dopa-responsive dystonia, which has recently been linked with mutations in the gene for GTP cyclohydrolase I [29].
• This locus is distinct from the hyperphenylalaninemia locus on chromosome 14 and the locus for tyrosine hydroxylase on chromosome 7 [30].
• There were no significant differences between left ventricular masses and systemic pressures, and there was no observed evidence of systemic hypertension in kidney sections between wild-type and hph-1 [31].

Analytical, diagnostic and therapeutic context of hph1

• Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria [32].
• The initial symptomatology of the mutant phenotype suggests this mutant may represent a useful animal model for the study of hyperphenylalaninemia in man [33].
• A quantitative double-label in situ hybridization technique was used to examine CNS GTPCH mRNA expression within serotonin, dopamine, and norepinephrine neurons of male and female wild-type and hph-1 mice [16].
• We used these data to establish a PCR method for genotyping wild type, hph-1 and heterozygote mice, and found that heterozygote animals have partial tetrahydrobiopterin deficiency [34].
• 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 [35].

References