Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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A novel subtype of patients with mutations in the phenylalanine hydroxylase (PAH) gene that show a positive response during a tetrahydrobiopterin (BH4) loading test has recently been recognized. These studies suggest that a number of phenylketonuric (PKU) patients may benefit from BH4 substitution, eliminating the need of life-long dietary restrictions. In our unit, we performed BH4 overload tests in 50 PAH-deficient patients. Overall, 38% of the patients had a positive response, mostly MHP and mild PKU patients, all with at least one missense mutation with presumed residual activity. Seven of the patients that required dietary restrictions have received treatment with BH4 from 5 to 18 months. All the patients included in the long-term treatment protocol had a mild PKU phenotype. BH4 therapy began at 10 mg/kg/day and changes were made over time depending on Phe levels. All patients at least doubled their protein ingestion and some could follow a completely free diet. Patients with a smaller decrease in Phe levels during the BH4 overload required higher BH4 doses and/or dietary restrictions to maintain adequate Phe levels over time. The genotype and the potential mechanisms underlying BH4 responsiveness and interindividual differences in pharmacokinetics of the administered cofactor are probably the basis for the differences in prolonged treatment.
Mol Genet Metab 2005 Dec
PMID:Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: evolution of seven patients on long-term treatment with tetrahydrobiopterin. 1616 89

Tetrahydrobiopterin (BH4) responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) gene was found during neonatal screening for PKU. This study determined blood BH4 and phenylalanine in two patients with hyperphenylalaninemia following oral load with BH4 10 mg/kg. Our patients underwent neonatal screening for PKU, had normal biopterin metabolism and their PAH mutations were determined. Peak plasma biopterin levels in Case 1, which were reached at between 2 and 4h after loading, were 612, 297, and 178 nmol/L at age 30 days, 55 days, and 19 months, respectively, and the maximum phenylalanine decreasing rates, which were found at 24h, were 54, 16, and 4%, respectively. In Case 2, peak plasma biopterin levels were 747 and 327 nmol/L at age 20 and 55 days, respectively, and the maximum phenylalanine decreasing rates were 39 and 32%, respectively. In the BH4 loading test, the peaks of BH4 in both patients lowered ( approximately 50%), on the same dose schedule of BH4, as patients got older.
Mol Genet Metab 2005 Dec
PMID:Plasma biopterin levels and tetrahydrobiopterin responsiveness. 1618 15

Tetrahydrobiopterin (BH4), the natural cofactor of phenylalanine hydroxylase (EC 1.14.16.1), can reduce blood phenylalanine (Phe) in BH4 sensitive patients with hyperphenylalaninemia (McKuisick 261600). We report on the long-term treatment of eight patients with mild and classical phenylketonuria (blood Phe levels maximum blood Phe levels between 771 and 1500 micromol/L) using BH4 at a dosage of 8-12 mg/kg BW per day. In all patients reduction of blood Phe was >30% after BH4 loading test. Three patients were treated from birth by BH4 only, five after initial low Phe dietary treatment. Seven of them continue to be on BH4 treatment only, one has a relaxed low protein diet. No side effects could be observed (longest observation time 5 years), somatic and psychomotor development were normal. The main problem of BH4 treatment is finding an optimal dosage at different ages and an under special conditions like infectious diseases. There is evidence that in some patients BH4 treatment may allow a more relaxed low protein diet showing positive effects on weight gain and quality of life. Further controlled studies are necessary not only to rule out any side effects but also for optimizing treatment strategies with BH4 treatment in mild phenylketonuria.
Mol Genet Metab 2005 Dec
PMID:Long-term treatment of patients with mild and classical phenylketonuria by tetrahydrobiopterin. 1624 84

Mutation spectrum of phenylalanine hydroxylase (PAH) gene in patients with phenylketonuria (PKU) in Northern China is described with a discussion on genotype-phenotype correlation. By using PCR/SSCP and DNA sequencing, all exons of PAH gene in the 185 unrelated patients with PKU from Northern China were studied. A total of 70 different mutations, including 42 missense, 12 splice, 7 nonsense, 5 deletion, 3 insertion, and 1 silence/splice mutations, were detected in 349/370 mutant alleles (94.3%). Deletion, insertion, and frameshift mutations were found for the first time in China PKU patients. The mutations R243Q, EX6-96A>G, R111X, Y356X, and R413P were the prevalent mutations with relative frequencies of 22.2, 11.1, 8.7, 6.5, and 6.5%, respectively. Fifteen novel mutations were identified in this study: I38fsX19, IVS4+3G>C, Y154H, R157K, R157I, T200fsX6, Q267H, Q267E, F302fsX39, G346R, S349A, L367L, R400K, IVS12+4A>G, and IVS12+6T>A. Each of them occurs at very low frequency (0.3-1.1%). The mutation spectrum of PKU in Chinese is similar to other Asian populations but significantly different from European populations. Altogether, 70 different mutations are found in 109 genotypes distributed among 185 PKU patients. As shown by the analysis, the predicted residual activity found in the majority of PKU individuals match their in vivo phenotypes, though evidence is also found for both phenotypic inconsistencies among subjects with similar genotypes and discordance between the in vitro and in vivo effects of some mutant alleles. The study enables us to construct a national database in China serving as a valuable tool for genetic counseling and prognostic evaluation of future cases of PKU.
Mol Genet Metab 2005 Dec
PMID:Phenylketonuria mutations in Northern China. 1625 86

Patients with tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency may benefit from BH4 therapy instead or in addition to the low-phenylalanine diet. Different loading test protocols are currently used to detect these patients. As a consequence, data on the rate of BH4-responsiveness within patients with mild phenylketonuria (PKU) and/or more severe phenotypes show high variation and a more sensitive and standardised BH4 loading test protocol needs to be defined. We modified the current standard BH4 loading test (20 mg/kg) to a second administration of 20 mg/kg after 24 h and extended blood sampling to 48 h in 24 patients with PAH deficiency. Using this extended loading test (2 x 20 mg BH4/kg), the rate of BH4-responsiveness was calculated at 8, 24, and 48 h after BH4 administration. We defined three groups of patients: "rapid responders" in 10/24 patients (4 mild HPA, 2 mild PKU, 2 moderate PKU, and 2 classic PKU), "moderate responders" in 4/24 patients (4 classic PKU), and "slow responder" in 4/24 patients (4 mild PKU). Six out of 24 patients (1 mild HPA, 1 moderate PKU, and 4 classic PKU) were found to be "non-responder." Individual phenylalanine profiles show variations in responsiveness at different time points and sampling over 48 h was more informative than over 24h in patients with mild and moderate PKU compared to mild HPA. Analysis of BH4 loading tests in 209 patients with the standard BH4 loading test protocol confirms only minor importance of the 24 h response: the rate of responsiveness to BH4 after 24 h was shown to be equal to or even lower than after 8h among most phenotypes. However, extension of the BH4 loading test to 48 h and repeated BH4 administration seems to be useful to detect BH4-responsiveness in more severe phenotypes and allows detecting "slow responders" who may benefit from BH4 therapy.
Mol Genet Metab 2005 Dec
PMID:Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria: a pilot study. 1629 3

Tetrahydrobiopterin (BH4) supplementation in patients with BH4-responsive phenylalanine hydroxylase (PAH) deficiency is an alternative to low-phenylalanine diet. To further investigate hepatic BH4-responsiveness, oral administration of 50 mg BH4/kg/day for 5 weeks was performed in wild-type mice. We observed a 2-fold increase in PAH protein by quantitative Western blot analysis and a 1.7-fold increase in enzyme activity, but no change in Pah-mRNA expression by quantitative real-time PCR analysis in treated mice compared to controls. Our findings support the proposed chemical-chaperone effect of BH4 to protect PAH.
Mol Genet Metab 2005 Dec
PMID:Stimulation of hepatic phenylalanine hydroxylase activity but not Pah-mRNA expression upon oral loading of tetrahydrobiopterin in normal mice. 1629 4

The larva of the swallowtail butterfly Papilio xuthus changes its body markings during the fourth ecdysis. We found that stage-specific cuticular black markings are mainly regulated by co-localization of two melanin synthesis enzymes; tyrosine hydroxylase (TH) and dopa decarboxylase (DDC). TH converts tyrosine to dihydroxyphenylalanine (dopa), and tyrosine itself is converted from phenylalanine by phenylalanine hydroxylase (PAH). Guanosine triphosphate cyclohydrolase I (GTPCHI) is essential for the synthesis of tetrahydrobiopterin (BH4) that is a cofactor of TH and PAH. In this report, we found that a GTPCHI inhibitor prevents pigmentation in cultured integuments, suggesting that the GTPCHI activity is also involved in cuticle pigmentation. We have cloned GTPCHI and PAH cDNAs from P. xuthus and investigated their spatial expression patterns in epidermis by whole-mount in situ hybridization. There are two isoforms of GTPCHI in larval epidermis (GTPCHIa and GTPCHIb). GTPCHIa is expressed at the black markings of the subsequent instar, similar to TH, whereas GTPCHIb is expressed uniformly, similar to PAH. This suggests that the region-specific expression of GTPCHIa supplies sufficient BH(4) reinforcing the TH activity in black marking area. Our results imply that larval markings are regulated by not only melanin synthesis enzymes but also the cofactor supplying enzyme.
Insect Biochem Mol Biol 2006 Jan
PMID:Expression of one isoform of GTP cyclohydrolase I coincides with the larval black markings of the swallowtail butterfly, Papilio xuthus. 1636 Sep 51

4a-Hydroxy-tetrahydrobiopterin dehydratase/DCoH is a bifunctional protein. In the cytoplasm it is an enzyme required for the regeneration of tetrahydrobiopterin, an essential cofactor for phenylalanine hydroxylase. In the nucleus it functions as a transcriptional coactivator by forming a 2:2 heterotetramer with the hepatic nuclear factor HNF1alpha (HNF1). Patients with a deficiency of dehydratase activity have elevated levels of phenylalanine, and accumulate 7-pterins due to degradation of its substrate 4a-hydroxy-tetrahydrobiopterin. Curiously, the hyperphenylalaninemia is transient, and no defects in the transcriptional coactivator function have been reported. Recently, a human isozyme, dehydratase/DCoHalpha, has been detected which shares 60% identity with dehydratase/DCoH. This investigation was undertaken to ascertain if dehydratase/DCoHalpha has the pre-requisite properties to compensate in individuals lacking an active form of DCoH. DCoHalpha demonstrated the ability to quantitatively alter HNF1-dependent DNA-binding in vitro whereas DCoH was ineffective in vitro. This characteristic, due to the presence of dimeric DCoHalpha, demonstrates that DCoHalpha does not require any additional mammalian regulation process to alter DNA binding and therefore, may be more effective than DCoH at low concentrations. The dehydratase activity of each isoform was measured by a direct spectrophotometric assay. Km and Vmax for DCoHalpha were both 2-3 times higher than for DCoH, thus leaving the catalytic efficiency (Vmax/Km) the same for both enzymes. In conclusion, the properties of dehydratase/DCoHalpha are consistent with the hypothesis that the activity of this isozyme could account for the relatively mild symptoms reported for patients with a defect in dehydratase/DCoH.
Mol Genet Metab 2006 May
PMID:Can the DCoHalpha isozyme compensate in patients with 4a-hydroxy-tetrahydrobiopterin dehydratase/DCoH deficiency? 1642 49

The role of a polypeptide loop in tyrosine hydroxylase (TyrH) whose homolog in phenylalanine hydroxylase (PheH) takes on a different conformation when substrates are bound has been studied using site-directed mutagenesis. The loop spans positions 177 to 191; alanine was introduced into those positions, introducing one alanine substitution per TyrH variant. Mutagenesis of residues in the center of the loop resulted in alterations in the KM values for substrates, the Vmax value for dihydroxyphenylalanine (DOPA) synthesis, and the coupling of tetrahydropterin oxidation to tyrosine hydroxylation. The variant with the most altered KM value for 6-methyltetrahydropterin was TyrH F184A. The variants with the most affected K(tyr) values were those with substitutions in the center of the loop, TyrH K183A, F184A, D185A, P186A and D187A. These five variants also had the most reduced Vmax values for DOPA synthesis. Alanine substitution in positions 182-186 resulted in lowered ratios of tyrosine hydroxylation to tetrahydropterin oxidation. TyrH F184Y and PheH Y138F, variants with the residue at the center of the loop substituted with the residue present at the homologous position in the other hydroxylase, were also studied. The V/K(tyr) to V/K(phe) ratios for these variants were altered significantly, but the results did not suggest that F184 of TyrH or Y138 of PheH plays a dominant role in determining amino acid substrate specificity.
J Mol Biol 2006 Jun 02
PMID:A flexible loop in tyrosine hydroxylase controls coupling of amino acid hydroxylation to tetrahydropterin oxidation. 1661 90

In order to determine the phenylketonuria (PKU) mutation spectrum in the population of Minas Gerais State, Brazil, 78 unrelated PKU patients found by the neonatal screening program from 1993 to 2003 were tested for nine phenylalanine hydroxylase mutations. These mutations were selected due to their high frequencies in other Brazilian populations and in Portugal, where the largest contingent of the Caucasian component of the Brazilian population originated from. The most frequent mutations were V388M (21%), R261Q (16%), IVS10nt11 (13.4%), I65T (5.7%), and R252W (5%). The frequencies of the other four mutations (R261X, R408W, Y414C, and IVS12nt1) did not reach 2%. By testing these nine mutations, we were able to identify 64% of the PKU alleles in our sample. V388M frequency was higher than in any other known population and almost three times larger than that observed in Portugal, probably reflecting genetic drift. The mutation profile, as well as the relative frequency of the different mutations, suggest that the Minas Gerais population more closely resembles that of Portugal than do the other Brazilian populations that have already been tested.
Genet Mol Res 2006 Mar 31
PMID:Frequencies of phenylalanine hydroxylase mutations I65T, R252W, R261Q, R261X, IVS10nt11, V388M, R408W, Y414C, and IVS12nt1 in Minas Gerais, Brazil. 1675 93


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