Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 25-year-old woman with mild hyperphenylalaninemia developed disabling depression and panic attacks. The mutations on the phenylalanine hydroxylase gene indicated that she might be responsive to tetrahydrobiopterin therapy. Mutation analyses were performed by the John F. Kennedy Institute in Glostrup, Denmark. The response to tetrahydrobiopterin therapy was impressive at an oral dose of 50 mg twice a day. A 25-year-old woman with mild hyperphenylalaninemia due to a PAH mutation of IVS12nt1g-->a/E390G has been treated for 1 year with BH4 therapy. A maintenance dosage of only 100 mg/day has resulted in significant improvement of depression and panic attacks, with discontinuation of psychotropic medication.
Mol Genet Metab 2002 Mar
PMID:Mental illness in mild PKU responds to biopterin. 1191 42

Hepatocyte nuclear factor 1 alpha (HNF1alpha) is a transcription factor that is expressed in liver, pancreas, kidney and intestine. 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. The renal phenotype involves a defect in renal proximal tubule reabsorption, leading to polyuria, glucosuria, aminoaciduria and phosphaturia. We investigated the expression of genes encoding members of the sodium/phosphate cotransporter (Na(+)/Pi) family (namely Npt1, Npt2, Npt4 and Ram1). We show that Npt1 and Npt4 genes were expressed at reduced levels in the kidneys of HNF1alpha -/- mice, whereas the expression of Npt2, the major renal phosphate transporter, was not affected. Analysis of the Npt1 genomic sequence revealed the existence of several alternative promoters activated in liver and/or in kidney. All of these were down-regulated in the kidneys of HNF1alpha -/- animals. Several HNF1alpha binding sites (BS) play an important role in the transcriptional control of this locus, including low-affinity HNF1 BSs localised in a DNase I hypersensitivity site (HSS3). Transient transfection experiments confirmed that HNF1alpha directly transactivates the Npt1 promoter and that the HSS3 region contributes to this activation.
J Mol Biol 2002 Oct 04
PMID:Hepatocyte nuclear factor 1 alpha controls renal expression of the Npt1-Npt4 anionic transporter locus. 1236 19

Hyperphenylalaninemia (HPA), due to a deficiency of phenylalanine hydroxylase (PAH) enzyme, is caused by mutations in the PAH gene. Molecular analysis in 23 Italian patients with PAH deficiency identified two novel (P281R, L287V) and 20 previously described genetic lesions in the PAH gene. The detection of the A403V amino acid substitution in combination with null mutations in patients with BH4-responsive PAH deficiency leads us to correlate it with BH4 responsiveness.
Mol Genet Metab 2002 Nov
PMID:Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia. 1240 76

A series of radioactive catastrophes (from 1948 to 1967) in the Southern Urals in the USSR led to intensive environmental contamination. Radioactive wastes were dispersed over the 20000 km(2) territory of four provinces-Chelyabinsk, Sverdlovsk, Tyumen' and Kurgan-due to the activity of the military facility that was built in 1948 for the production of nuclear bomb plutonium. The results of 50 years of investigations into the consequences of these disasters allow a general picture of the events that occurred to be reconstructed and allow the medical consequences of the irradiation of about half a million residents to be depicted. However, due to the atmosphere of secrecy and inadequate medical procedures, the results of medical studies of radiation victims are scant. The current protocols present a unique opportunity to study the DNA damage at the nucleotide resolution level in the genome of inhabitants of the given region, who presumably received chronic doses of irradiation. Studies were conducted through the direct sequencing of genes after their PCR-amplification and preselection of allegedly mutated DNA molecules. The regions of two genes have been sequenced: D1 dopamine receptor gene (subfamily of the G-protein coupled receptor L-DOPA genes) and the intron 12 of the gene for phenylalanine hydroxylase (PAH) responsible for phenylketonuria or hyperphenylalaninemia. Six point mutations (four presumably new) were found in the D1 gene of 42 persons and five polymorphic loci (two of which are widespread and three are unique) were revealed in the PAH gene. One of two widespread mutations is a deletion, and the other four are substitutions. Mutations in the controls were not found.
Comp Biochem Physiol A Mol Integr Physiol 2002 Nov
PMID:Radiation accidents in the Southern Urals (1949-1967) and human genome damage. 1244 29

Tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) is a recently described variant of phenylalanine hydroxylase deficiency. In contrast to patients with classical phenylketonuria, these patients respond to BH(4) loading tests (20mg/kg) with decrease of plasma phenylalanine levels 4 and 8 h after administration and they can be treated with BH(4) monotherapy. We retrospectively evaluated 1,919 loading tests from 33 different countries performed in our laboratory between 1988 and 2002 of which 278 loading tests were performed with 6R-BH(4), which is about 33% more active than the formerly used 6R,S-BH(4). The loading tests were performed between the ages of one week and 4.6 years, using 2.6-30.0 mg 6R,S- or 6R-BH(4)/kg. Plasma phenylalanine levels before the test ranged from 121 to 4,705 micromol/L. We calculated the phenylalanine "hydroxylation rate" 4 and 8 h after BH(4) administration and plotted the slope of the hydroxylation rate against the phenylalanine levels at time 0. The slope was greater than 3.75 in 65, 74, 33, 17, 0, and 10% of patients with basal phenylalanine levels of 120-400, 400-800, 800-1,200, 1,200-1,600, 1,600-2,200, and >2,200 micromol/L, respectively, when loaded with 20 mg 6R-BH(4)/kg (p>0.0001). This is 5-20 times higher compared with tests using 6R,S-BH(4) or lower doses of BH(4). More than 70% of patients with mild HPA (<800 micromol/L) are found to be BH(4) responders. Therapy with BH(4) (approximately 10mg/kg/day) was initiated in several patients instead of a low-phenylalanine diet, resulting in much better treatment compliance. Our data further demonstrate that BH(4) loading tests can only distinguish between BH(4) responders and non-responders. To differentiate between BH(4) and phenylalanine hydroxylase deficiencies additional tests are essential.
Mol Genet Metab 2002 Dec
PMID:High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002. 1246 76

Since 1999 an increasing number of patients with phenylalanine hydroxylase (PAH) deficiency are reported to be able to decrease their plasma phenylalanine (Phe) concentrations after a 6R-tetrahydrobiopterin (BH(4)) challenge. The majority of these patients have mild PKU or MHP (mild hyperphenylalaninemia) and harbour at least one missense mutation in the PAH gene associated with this phenotype. The rate of decrease and the lowest achieved Phe level vary between patients with different genotypes but appears to be similar in patients with the same genotype. A number of the mutations associated with BH(4)-responsiveness have been studied in an 'in vitro' eukaryotic cell expression system leading to biosynthesis of a mutant PAH enzyme with some residual activity. Patients bearing mutations that cause severe structural distortion in the expressed protein (loss of function mutations), leading to undetectable PAH activity, are not responsive to BH(4). These observations suggest that residual PAH activity (in vitro) is a prerequisite for BH(4)-responsiveness. However, an in vitro residual PAH activity is not a guarantee for in vivo BH(4)-responsiveness. Mechanisms behind this responsiveness could be relieve of decreased binding affinity for BH(4), BH(4)-mediated increase of PAH gene expression or stabilization of the mutant enzyme protein by BH(4). BH(4)-responsive PAH-deficient patients have only been reported since 1999. For the western countries this is explained by the fact that the manufacturer changed the diastereoisomeric purity of the BH4 preparation from 69% of the natural 6R-BH4 (31% of 6S-BH4) to 99.5% 6R-BH4. The new findings on BH(4)-responsiveness may be of clinical relevance because these patients can be treated with BH(4) with concomitant relief or withdrawal of the burdensome PKU diet. These observations warrant further clinical studies to assess efficacy, optimal dosage, and safety of BH(4) treatment in this group. The data strongly emphasize the necessity of the BH(4) loading test in patients detected in the newborn PKU screening.
Mol Genet Metab 2003 Feb
PMID:Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state of the art. 1261 80

Phenylketonuria (or PKU) is a well-known and widespread genetic disease for which many countries perform newborn screening, and life-long dietary restriction is still the ultimate and effective therapy. However, the diet is complicated, unpalatable, and expensive. The long-term effects of diet discontinuation in adults, except for the serious adverse effects of maternal hyperphenylalaninemia upon the developing fetus, have not been systematically studied, but cognitive decline and neurologic abnormalities have been anecdotally reported. Thus, alternative approaches for PKU therapy, including gene therapy, must be further explored. Here we summarize past present nonviral and viral gene transfer approaches, both in vitro studies and preclinical animal trials, to delivering the PAH gene into liver or other organs as potential alternatives to life-long phenylalanine-restricted dietary therapy.
Mol Genet Metab 2004 Jan
PMID:State-of-the-art 2003 on PKU gene therapy. 1472 84

Tetrahydrobiopterin (BH(4)) is widely used as a therapeutic agent in patients with BH(4) deficiencies and mild forms of phenylketonuria (PKU) and there is an increasing need for the measurement of its plasma concentrations in patients with cardiovascular disorders. We measured BH(4) and total biopterin in dithioerythritol (DTE) pretreated plasma from four adults after oral administration of BH(4) (2, 10, and 20mg/kg body weight) using the differential iodine oxidation method. About 80% (range 64.8-92.2% ) of total biopterin was found as BH(4) when analyzed immediately after blood sampling. Compared with ascorbic acid as an antioxidant, DTE was more protective against oxidation of BH(4), particularly in samples stored over a period of 8 months. Without antioxidant (DTE or ascorbic acid) almost no BH(4) was detected. Furthermore, BH(4) and total biopterin were measured at different time intervals (up to 33 h after oral administration) and pharmacokinetic parameters T(max) (1-4h), C(max) (258.7-259.0 nmol/L biopterin at a dosage of 10mg/kg), and area under the curve (AUC=1708-1958 nmol(*)h/L up to T=10h) were estimated. The elimination half-life time was calculated to be 3.3-5.1h. Doubling the BH(4) dosage to 20mg/kg resulted in 60% higher AUC while sublingual BH(4) application (2mg/kg) resulted in 58-76% higher BH(4) plasma concentrations when compared with oral administration. These preliminary data suggest that in patients with BH(4) cofactor defects and BH(4)-responsive phenylalanine hydroxylase deficiency, BH(4) should be given in at least two to three daily doses and that sublingual administration may lower the required BH(4) dosage and subsequently the cost of treatment. Due to inter individual differences in pharmacokinetic properties, in some patients with hyperphenylalaninemia and mild PKU plasma BH(4) levels may be not high enough to fully activate the liver phenylalanine hydroxylase and thus lower blood phenylalanine levels. Assessment of plasma BH(4) or total biopterin concentrations may be a good way to control the efficacy of the loading test.
Mol Genet Metab 2004 Jan
PMID:Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration. 1472 90

Tetrahydrobiopterin (BH(4)) is a required cofactor for the enzymatic activity of phenylalanine hydroxylase (PAH) and is synthesized de novo from GTP in several tissues. Heterologous expression of PAH in tissues other than liver is a potential novel therapy for human phenylketonuria that is completely dependent upon BH(4) supply in the PAH-expressing tissue. 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. In this report, the fate of intravenously administered BH(4) is examined. The conclusions are that (1) BH(4) administered intravenously is rapidly taken up by liver and kidney, and (2) uptake of BH(4) into muscle is relatively low. The levels of BH(4) achieved in skeletal muscle following IV injection are only 10% of the amount expected were BH(4) freely and equally distributed across all tissues. The half-life of BH(4) in muscle is approximately 30 min, necessitating repeated injections to maintain muscle BH(4) content sufficient to support phenylalanine hydroxylation. The efficacy of heterologous muscle-directed gene therapy for the treatment of PKU will likely be limited by the BH(4) supply in PAH-expressing muscle.
Mol Genet Metab 2004 Jan
PMID:The fate of intravenously administered tetrahydrobiopterin and its implications for heterologous gene therapy of phenylketonuria. 1472 91

Individuals with phenylketonuria (PKU) have been reported to have altered trace mineral status. In this study, we evaluated in a murine PKU model whether protein level and level of phenylalanine (PHE) restriction could modulate iron, copper, and zinc status. Fifty-four male weanling PKU and control mice were assigned to receive for 56 days an elemental low or normal protein diet; PKU mice also were assigned to receive PHE restriction (treated) or no restriction (untreated). PHE-restricted mice consumed a prescribed dietary PHE to maintain plasma PHE concentrations between 120 and 480 micromol/L. PHE-unrestricted and control mice received equal amounts of dietary PHE. Intestinal and hepatic copper, iron, and zinc were measured at day 56 and fecal minerals measured at baseline and day 56. Mean plasma PHE concentrations were significantly greater in PKU PHE-unrestricted versus PKU PHE-restricted mice and control mice. Mean intestinal weights when normalized for body weight were significantly greater in PKU mice versus control mice. PKU PHE-unrestricted mice had significantly lower hepatic copper and zinc than PKU PHE-restricted mice, and significantly greater hepatic iron than control and PKU PHE-restricted mice. PKU PHE-unrestricted mice on a low protein diet had hepatic iron concentrations about 1.5 times that of the other mice. Fecal iron concentrations in all mice were significantly greater at day 56 than at baseline. No animal group effects or protein level effects were found for fecal copper, iron, or zinc contents. We conclude that hyperphenylalaninemia alters the metabolism of iron, copper, and zinc in PKU mice.
Mol Genet Metab 2004 May
PMID:Plasma phenylalanine concentrations are associated with hepatic iron content in a murine model for phenylketonuria. 1511 Mar 26


<< Previous 1 2 3 4 5 6 7 8 9 Next >>