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

Hippocampal N-methyl-D-aspartate receptors (NMDARs) are thought to be involved in the regulation of memory formation and learning. Investigation of NMDAR function during experimental conditions known to be associated with impaired cognition in vivo may provide new insights into the role of NMDARs in learning and memory. Specifically, the mechanism whereby high concentrations of L-phenylalanine (L-Phe) during phenylketonuria (>1.2 mM) cause mental retardation remains unknown. Therefore, the effects of L-Phe on NMDA-activated currents (I(NMDA)) were studied in cultured hippocampal neurons from newborn rats using the patch-clamp technique. L-Phe specifically and reversibly attenuated I(NMDA) in a concentration-dependent manner (IC(50) = 1.71 +/- 0.24 mM). In contrast, L-tyrosine (L-Tyr), an amino acid synthesized from L-Phe in normal subjects, did not significantly change I(NMDA). Although the L-Phe-I(NMDA) concentration-response relationship was independent of the concentration of NMDA, it was shifted rightward by increasing the concentration of glycine. Consistent with an effect of L-Phe on the NMDAR glycine-binding site, L-Phe (1 mM) did not attenuate I(NMDA) in the presence of D-alanine (10 microM). Furthermore, L-Phe significantly attenuated neither glutamate-activated current in the presence of MK-801, nor current activated by AMPA. The finding that L-Phe inhibits specifically NMDAR current in hippocampal neurons by competing for the glycine-binding site suggests a role for impaired NMDAR function in the development of mental retardation during phenylketonuria and accordingly an important role for NMDARs in memory formation and learning.
Mol Psychiatry 2002
PMID:Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria. 1198 79

Several reports indicate that biopterin and folate pathways may interact. We examined folate metabolism in PKU patients where hyperphenylalaninaemia leads to a likely excess of THB. We found an increase in total HPLC determined red cell folate in PKU (p=0.0422): specifically, there was an increase in total formyl-H(4)folate (p=0.0002) and H(4)folate (p< or =0.0001), and decrease in total 5-methyl-H(4)folate in PKU patients. At the level of individual oligo-gamma-glutamyl coenzymes, we found that formyl-H(4)folate polyglutamates were virtually all increased in PKU (p=0.0223, 0.0004, 0.0004, 0.0012, and 0.0008 for di-, tri-, tetra-, penta-, and deca-gamma-glutamyl formyl-H(4)folate coenzymes, respectively). Hcy levels did not differ between clinical groups, indicating that folate dependent-Hcy remethylation is not compromised as a consequence of an altered PKU folate disposition. In nature, pentaglutamyl folates are considered the metabolically favoured coenzymes (optimum K(m) for dependent enzymes). The presented data support this-we found that red cell pentaglutamates gave the best measure of metabolism; pentaglutamyl formyl-H(4)folate increased in PKU (p=0.0012) and related methenyls behaved similarly, while, pentaglutamyl 5-methyl-H(4)folate and pentaglutamyl H(4)folate decreased (p< or =0.0001 and 0.0265, respectively). Furthermore, pentaglutamates showed the best correlations between one-carbon oxidation states of folate, as well as with Hcy (p=0.0003 r=-0.54, 95% CI; -0.724 to -0.272). That PKU might influence folate metabolism in some way is unsurprising: patients with DHPR deficiency accumulate DHB and develop secondary folate deficiency-responsive only to reduced folates, while CSF levels of THB are significantly correlated to monoamines and red cell folate in depression. Further studies to confirm the present findings and to ascertain precisely what mechanism operates in PKU that impacts upon folate homeostasis so profoundly are required.
Mol Genet Metab 2002 Aug
PMID:The impact of phenylketonuria on folate metabolism. 1220 35

Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase (PAH) and increased levels of phenylalanine. PAH requires the cofactor BH(4) to function and the rate-limiting step in the synthesis of BH(4) is GTP cyclohydrolase I (GTP-CH). The skin is a potential target tissue for PKU gene therapy. We have previously shown that overexpression of PAH and GTP-CH in primary human keratinocytes leads to high levels of phenylalanine clearance without BH(4) supplementation [Gene Ther. 7 (2000) 1971]. Here, we investigate the capacity of fibroblasts, another cell type from the skin, to metabolize phenylalanine. After retroviral gene transfer of PAH and GTP-CH both normal and PKU patient fibroblasts were able to metabolize phenylalanine, however, in lower amounts compared to genetically modified keratinocytes. Further comparative analyses between keratinocytes and fibroblasts revealed a higher copy number of transgenes in keratinocytes and also a higher metabolic capacity.
Mol Genet Metab 2002 Aug
PMID:Comparison of epidermal keratinocytes and dermal fibroblasts as potential target cells for somatic gene therapy of phenylketonuria. 1220 36

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

Newborn screening has existed for approximately four decades. During that period of time, newborn screening has evolved conceptually from a laboratory test for a single disorder, phenylketonuria (PKU), to a multi-part public health system involving education, screening, diagnostic follow-up, treatment/management, and system evaluation. At a time when newborn screening is recognized as a model for predictive medicine, it also faces critical challenges that will determine its future credibility and viability. In order to understand these challenges, it is helpful to review briefly the history of newborn screening.
Mol Genet Metab 2002 Dec
PMID:Newborn screening: rationale for a comprehensive, fully integrated public health system. 1246 71

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

Denaturing high-performance liquid chromatography (DHPLC) is a sensitive and fast method for the detection of mutations which has been successfully used for mutation screening in several disease-related genes. Phenylketonuria (PKU, OMIM* 261600; McKusick 1986) is one of the most common autosomal recessive disorders in Europe. Mutations in the PAH gene mainly involve point mutations. In this study we report the successful use of DHPLC to analyse rapidly the complete coding sequence of the PAH gene in a total of 125 unrelated patients with PKU.
Mol Genet Metab 2003 Mar
PMID:DHPLC mutation analysis of phenylketonuria. 1264 65

Phenylketonuria (PKU) is an autosomal recessive disorder due to phenylalanine hydroxylase (PAH) deficiency. The PAH gene, located at 12q22-q24.1, includes about 90kb and contains 13 exons. To date, more than 420 different alterations have been identified in the PAH gene. To determine the nature and frequency of PAH mutations in PKU patients from South Brazil, mutation analysis was performed on genomic DNA from 23 unrelated PKU patients. The 13 exons and flanking regions of the PAH gene were amplified by PCR and the amplicons were analyzed by single strand conformation polymorphism (SSCP). Amplicons that showed abnormal migration patterns were analyzed by restriction endonuclease digestion and/or sequencing. Twenty-two previously reported mutations were identified including R261X, R408W, IVS2nt5g-->c, R261Q, and V388M. Polymorphisms were observed in 48.8% of the PKU patients, the most frequent being IVS2nt19t-->c, V245V, and IVS12nt-35c-->t. In addition, two novel sequence variants were identified: 1378g-->t in the 3(')-untranslated region in exon 13 which may be disease-causing and an intron 12 polymorphism, IVS12nt-15t-->c. The mutation spectrum in the patients from Southern Brazil differed from that observed in patients from other Latin American countries and further defined the molecular heterogeneity of this disease.
Mol Genet Metab 2003 May
PMID:Molecular characterization of phenylketonuria in South Brazil. 1276 42

Phenylketonuria (PKU) is a metabolic disorder that results from a deficiency of hepatic phenylalanine hydroxylase (PAH). Identification of the PKU genotype is useful for predicting clinical PKU phenotype. More than 400 mutations resulting in PAH deficiency have been reported worldwide. We used a genedetecting instrument to identify the nine prevalent Japanese mutations in the PAH gene among 31 PKU patients as a preliminary study. This instrument can automatically detect mutations through the use of allelespecific oligonucleotide (ASO) capture probes, and gave results comparable to those of sequencing studies. Each country has uniquely prevalent and specific mutations causing PKU, and less than 50 types of such mutations are generally present in each country. Early genotyping of PKU makes it possible to identify the phenotype and select the optimal therapy for the disease. For early genotyping, the instrumental method described here shortens the time required for genotyping based on mRNA and/or genomic DNA of PKU parents.
Mol Biotechnol 2003 Jul
PMID:Rapid single-base mismatch detection in genotyping for phenylketonuria. 1277 91


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