Gene/Protein Disease Symptom Drug Enzyme Compound
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Phenylketonuria (PKU) is one of the few genetic diseases in which mental retardation can be prevented. Hence, diagnosis and treatment must be established early. PKU treatment consists of a phenylalanine-restricted diet supplemented with a phenylalanine-free mixture of amino acids. However, it is difficult to adhere to this diet. In the last decade, a better comprehension of the biochemistry, genetics and molecular basis of the disease, as well as the need for easier treatment, led to the development of several new therapeutic strategies for PKU. In the present study, we evaluated these new therapeutic options in terms of theoretical basis, methodologies, efficacy, and costs.
Genet Mol Res 2006 Mar 31
PMID:The time has come: a new scene for PKU treatment. 1675 95

Large gene deletions and duplications were analyzed in 59 unrelated phenylketonuria (PKU) patients negative for phenylalanine hydroxylase (PAH) mutations on one or both alleles from previous exon by exon analysis. Using the novel multiplex ligation-dependent probe amplification (MLPA) method, a total of 31 partial PAH deletions involving single exons were identified in 31 PKU patients. Nineteen cases exhibited deletion of exon 5, and 12 cases provided evidence for the deletion of exon 3. Subsequently, using restriction enzyme digestion and DNA sequencing, three different large deletions, EX3del4765 (12 cases), EX5del955 (2 cases) and EX5del4232ins268 (17 cases) were identified and confirmed by long-range PCR and by the analysis of aberrant transcripts. Altogether, the 31 large deletions presented account for 3% of all PAH mutant alleles investigated in Czech PKU patients. Bioinformatic analysis of three breakpoints showed that the mutation EX3del4765 had arisen through an Alu-Alu homologous recombination, whereas two other mutations-the EX5del955 and EX5del4232ins268, had been created by a non-homologous end joining (NHEJ). We conclude that MLPA is a convenient, rapid and reliable method for detection of intragenic deletions in the PAH gene and that a relatively high number of alleles with large deletions are present in the Slavic PKU population.
Mol Genet Metab 2006 Dec
PMID:Identification and characterization of large deletions in the phenylalanine hydroxylase (PAH) gene by MLPA: evidence for both homologous and non-homologous mechanisms of rearrangement. 1693 Oct 86

Deficient activity of the Dihydropteridine Reductase enzyme (DHPR; EC 1.5.1.34; OMIM 261630) is due to mutations in the Quinoid Dihydropteridine Reductase gene on 4p15.3 (QDPR; RefSeq NM_000320). It results in defective recycling of tetrahydrobiopterin (BH(4)) and homozygotes have a rare form of atypical Hyperphenylalaninaemia and Phenylketonuria (aPKU). The heterozygote frequency in the Maltese population is high at 3.3%. The more recently described and rarer type of BH(4) deficiency due to Sepiapterin Reductase enzyme deficiency (SR; EC 1.1.1.153; OMIM 182125), which presents as an atypical form of Dopa Responsive Dystonia (DRD) [L. Bonafe, B. Thony, J.M. Penzien, B. Czarnecki, N. Blau, Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia, Am. J. Hum. Genet. 69 (2001) 269-277; B.R.G. Neville, R. Parascandalo, S. Attard Montalto, R. Farrugia, A.E. Felice, A congenital dopa responsive motor disorder: a Maltese variant due to sepiapterin reductase deficiency, Brain 128 (Pt10) (2005) 2291-2296.] has also been identified at high frequency (4.6%) in this population. Two mutations, the c.68G>A in QDPR (p.G23D), and the new SPR, IVS2-2A>G mutation at the splice site consensus sequence in intron 2 of the Sepiapterin Reductase gene (SPR; RefSeq NM_003124) on 2p14-p12, were found to be the sole causative mutations in all the patients with DHPR deficiency and SR deficiency studied. All parents were heterozygotes for the corresponding mutation and showed no clinical symptoms. Three polymorphisms, c.96C>T (p.A32A), c. 345G>A (p.S115S) and c. 396G>A (p.L132L), have also been identified in the QDPR gene, defining four wild-type frameworks, useful in molecular epidemiology studies. The c. 68G>A mutation in QDPR was found only on framework I, suggesting a founder effect. In contrast no additional sequence diversity was found in the SPR gene whether in wild-type or mutant alleles which is also consistent with a founder effect.
Mol Genet Metab 2007 Mar
PMID:Molecular genetics of tetrahydrobiopterin (BH4) deficiency in the Maltese population. 1718 38

We have previously reported a transgene delivery system based on phiBT1 bacteriophage integrase that results in targeted insertion of transgenes into mammalian genomes, and its use in the delivery of murine phenylalanine hydroxylase (PAH) complementary DNA (cDNA) into the hepatocytes of male phenylketonuria (PKU) mice, leading to a complete and permanent correction of their hyperphenylalaninemic phenotype. In this study, we report only partial phenotypic correction in female PKU mice, even though hepatic PAH activities in both sexes after gene treatment were similar. Daily injections of tetrahydrobiopterin (BH4), an essential co-factor for phenylalanine hydroxylation, in the gene-treated females led to complete correction of their PKU phenotype. After gonadectomy, serum phenylalanine levels in the gene-treated females were reduced to normal, whereas those in the gene-treated males remained unchanged. The sterile gene-treated PKU mice were subjected to daily sex hormone injections. Whereas the estradiol-treated sterile males developed hyperphenylalaninemia, the dihydrotestosterone-treated sterile females remained normal phenylalaninemic. The results indicate that it is estrogen that suppresses the steady-state levels of BH4 in mouse hepatocytes that became limiting, which is the underlying mechanism for the observed sexual dimorphism in PKU mice after PAH gene treatment. Livers of the PAH gene-corrected PKU mice also appeared normal and without apparent pathologies.
Mol Ther 2007 Jun
PMID:Metabolic basis of sexual dimorphism in PKU mice after genome-targeted PAH gene therapy. 2773 55

Phenylketonuria (PKU, MIM 261600; EC 1.14.16.1) results from mutations in the phenylalanine hydroxylase (PAH) gene. Newborn metabolic disease screening uses blood dried on filter paper (DBS) to prospectively identify candidate newborns affected with PKU via an elevated concentration of phenylalanine. However, it is then important to confirm the specific category of PKU since classical PKU requires a stringent diet while milder categories may not require diet and a very important BH4-responsive category may be treated with the PAH cofactor 6R-tetrahydrobiopterin (BH4). Since there is a close genotype-phenotype correlation in PKU, determining the PAH genotype can be extremely important for therapy as well as prognosis. A simple and rapid method of accurately determining the PAH genotype would be a valuable addition to the diagnosis of PKU. Described herein is a means to identify variants in the PAH gene using high-resolution melt profiling, which compares the thermal denaturation profile of a patient sample to that of a control. Regions where the patient and control samples produce a common profile were not further evaluated, while those regions where the patient profile deviates from the control were assessed by DNA sequencing. Additionally described is a scheme utilizing redundant analysis with melt profile controls and a novel multiplex genotyping assay to triage deviation owing to known polymorphisms. Two mutations were identified in 93 of the 95 patients assessed and in the remaining two patients a single mutation was identified. Melt profiling provided 99% sensitivity to identify sequence variants in the PAH gene.
Mol Genet Metab 2007 Jul
PMID:Mutations in the phenylalanine hydroxylase gene identified in 95 patients with phenylketonuria using novel systems of mutation scanning and specific genotyping based upon thermal melt profiles. 1750 62

Protein and peptide therapeutics are of growing importance as medical treatments but can frequently induce an immune response. This work describes the combination of complementary approaches to map the potential immunogenic regions of the yeast Rhodosporidium toruloides phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) and to engineer the protein as a human therapeutic agent for the treatment of phenylketonuria (PKU), an inherited metabolic disorder. The identification of B and T cell epitopes on the PAL protein was performed by computational predictions based on the antigenicity and hydrophilicity of proteins, as well as by experimental epitope mapping using a PepSpots peptide array (Jerini AG). Human T cell epitope mapping was performed by applying the computational EpiMatrix algorithm (EpiVax, Inc.) for MHC Class I and Class II associated T cell epitopes on PAL, which predicts which sequences are associated with binding to several different HLA alleles, a requirement for antigen presentation and subsequent primary immune response. By chemical modification through PEGylation of surface lysine residues, it is possible to cover the immunogenic regions of a protein. To evaluate this strategy, we used mass spectrometry to determine which of the immunogenic epitopes are covered by the covalent PEGylation modification strategy. This approach has allowed us to determine whether additional lysines are needed in specific residue locations, or whether certain lysine residues can be removed in order to accomplish complete molecular coverage of the therapeutic enzyme.
Mol Genet Metab 2007 Aug
PMID:Structure-based epitope and PEGylation sites mapping of phenylalanine ammonia-lyase for enzyme substitution treatment of phenylketonuria. 1756 Aug 21

Blood phenylalanine (Phe) levels provide a practical and reliable method for the diagnosis and monitoring of metabolic status in patients with phenylketonuria (PKU). To assess the reliability of blood Phe levels as a predictive biomarker of clinical outcomes in the development of treatments for PKU, a systematic literature review and meta-analysis of published trials of PKU, which included Phe level and neurological and dietary compliance outcome measures, was conducted. Within-study correlations between Phe level and intelligence quotient (IQ) were extracted from 40 studies. Significant, proportional correlations were found during critical periods (from 0 to 12 years of age) for early-treated patients with PKU (r=-0.35; 95% confidence interval [CI]: -0.44 to -0.27), where each 100 micromol/l increase in Phe predicted a 1.3- to 3.1-point reduction in IQ. Similar significant correlations were observed between IQ and mean lifetime Phe level for early-treated patients (r=0.34; 95% CI: -0.42 to -0.25), where each 100 micromol/l increase in Phe predicted a 1.9- to 4.1-point reduction in IQ. Moderate correlations were found between concurrent Phe level and IQ for early-treated patients. In conclusion, these results confirm a significant correlation between blood Phe level and IQ in patients with PKU, and support the use of Phe as a predictive biomarker for IQ in clinical trials.
Mol Genet Metab
PMID:Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. 1759 52

Phenylketonuria (PKU) is a metabolic disorder secondary to a hepatic deficiency of phenylalanine hydroxylase (PAH) that predisposes affected children to develop severe and irreversible mental retardation. We have previously reported the complete and permanent correction of the hyperphenylalaninemic and hypopigmentation phenotypes in male, but not female, PKU mice after genome-targeted delivery of murine PAH (mPAH) complementary DNA (cDNA) in a phiBT1 bacteriophage integration system. Here we show that sequential administration of green fluorescent protein (GFP)- and red fluorescent protein (RFP)-expressing cassettes in the phiBT1 integration system led to distinct and non-overlapping populations of green and red fluorescent hepatocytes in vivo. The hyperphenylalaninemic and hypopigmentation phenotypes of female PKU mice were completely corrected after 10 weekly administrations of mPAH cDNA. Importantly, there was no apparent liver pathology in mice even after 10 consecutive administrations of the phiBT1 integration system. The results indicate that repeated administration of transgenes in the phiBT1 integration system can lead to their genome-targeted integration in a diverse population of hepatocytes and result in the elevation of transgene expression levels in a cumulative manner, which can be utilized to overcome insufficient transgene expression owing to low genome integration frequencies in a gene therapy paradigm for metabolic disorders.
Mol Ther 2007 Oct
PMID:Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. 2773 55

Glycomacropeptide (GMP) is a whey protein that contains no aromatic amino acids including phenylalanine (phe). The objective of this study was to make a variety of palatable, low-phe foods and beverages with GMP and to assess their acceptability by conducting consumer sensory studies in individuals with PKU. Results demonstrate acceptability of products made with GMP. GMP supplemented with limiting indispensable amino acids could provide an alternative protein source for individuals with PKU.
Mol Genet Metab
PMID:Acceptable low-phenylalanine foods and beverages can be made with glycomacropeptide from cheese whey for individuals with PKU. 1764 19

Some individuals with phenylketonuria (PKU) respond to pharmacologic treatment with tetrahydrobiopterin (BH(4)) by a reduction in the blood phenylalanine concentration. This can result in increased dietary tolerance for phenylalanine or, in rare instances, replacement of the phenylalanine-restricted diet. BH(4) is now available as sapropterin dihydrochloride under the name KUVAN, a formulation of natural BH(4). This commentary contains recommendations for determining responsiveness to sapropterin dihydrochloride. The recommendations include challenging with an initial daily dose of 20mg/kg and blood phenylalanine determinations pre-challenge and on days 1, 7, and 14 with the option of an additional continuation to day 28 if required to clarify whether a response has occurred. An algorithm depicting this recommendation for the challenge is included. The most widely accepted standard of response is > or = 30% reduction in the blood phenylalanine concentration, but a lower degree of response might also be considered clinically meaningful in some individual circumstances. Issues include the potential treatment of those with mild hyperphenylalaninemia who are not on diet, challenging neonates who have hyperphenylalaninemia identified by newborn screening, and the use of sapropterin dihydrochloride in treatment of maternal PKU pregnancies. These recommendations are intended to provide a basis for the use of sapropterin dihydrochloride in the treatment of PKU but may be altered after close observation of treated patients and carefully performed research.
Mol Genet Metab 2007 Dec
PMID:Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. 1803 98


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