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|Coordinate||87,570,226 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||phenylalanine hydroxylase|
|Synonym(s)||AW106920, OTTMUSP00000027786, PH, PKU, PKU1|
|Chromosomal Location||87,521,795-87,584,136 bp (+)|
|MGI Phenotype||Homozygotes for ENU-induced mutations of this gene have altered serum and urine phenylalanine levels and may display reduced body size, microcephaly, microphthalmia, decreased litter size, hypopigmentation, impaired balance/swimming, cognitive deficits, and environmentally-induced seizures.|
|Amino Acid Change||Leucine changed to Proline|
|Institutional Source||Beutler Lab|
L242P in Ensembl: ENSMUSP00000020241 (fasta)
|Gene Model||not available|
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||Autosomal Recessive|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||2016-05-13 3:09 PM by Stephen Lyon|
First observed in an ENU-mutagenized G3 female, the bronze phenotype is characterized by hypopigmentation of the fur, mild micropthalmia, and reduced body size. Although the fur of homozygous mice is black at birth, it becomes brown by approximately 5 weeks of age (Figure 1). Different mice show varying degrees of hypopigmentation. Homozygotes older than 6 months of age experience seizures if startled and after handling.
|Nature of Mutation|
The bronze mutation was mapped to Chromosome 10, and corresponds to a T to C transition at position 947 of the Pah cDNA, in exon 7 of 13 total exons.
The mutated nucleotide is indicated in red lettering, and results in a leucine to proline substitution at amino acid 242 of the Pah protein.
The human and mouse PAH proteins are 92% identical, and consist of 452 and 453 amino acids, respectively. Much of the research on phenylalanine hydroxylase has been carried out with the human protein and the discussion here will pertain to human PAH unless indicated. PAH exists in a pH-dependent equilibrium of homotetramers and homodimers (5). Like the other AAHs, PAH contains three domains, an N-terminal regulatory domain (amino acids 1-142), catalytic domain (amino acids 143-410), and a C-terminal tetramerization domain (amino acids 411-452) (Figure 3). The protein sequences of the catalytic domains of the three AAHs are highly conserved, but the regulatory domains are relatively more divergent (less than 14% sequence identity), reflecting different mechanisms of regulation. The crystal structures of several truncated forms of PAH have been solved [(6-11) and reviewed in (12)]. When the catalytic domains of these structures are superimposed, a composite full-length structural model can be constructed (13).
Like the other AAHs, PAH is an iron-dependent enzyme, requiring one iron atom per subunit for activity (23;24). Ferrous iron (Fe2+) is required for the hydroxylation reaction and is found in the active site at the start and finish of each catalytic cycle. The iron atom (Fe3+ in the form isolated for structural studies) is located on the floor of the active site, at the intersection of the channel and the active site pocket. It is coordinated by His285, His290, an oxygen atom in Glu330 (12;25), as well as three water molecules, all of which are arranged in an octahedral geometry. Hydroxylation by PAH also requires the cofactor BH4, which binds close to the catalytic iron and packs against a flexible loop formed by residues 247-251 (8;9). Most of the interactions are with the pyrimidine ring of the pterin, which also forms an aromatic π-stacking interaction with Phe254. BH4 hydrogen bonds with two of the water molecules coordinated to the iron atom, with Ala322, Gly247, Leu249, and Ser251; Glu286 forms the only electrostatic interaction between PAH and BH4. A large conformational change occurs upon binding of BH4 to PAH, in which residues 245-250 move towards the iron. In this position, O2 can form a bridge between iron and the pterin during the hydroxylation reaction. In addition to its interaction with the catalytic domain, BH4 also binds to the regulatory domain of PAH, serving to negatively regulate enzyme activity (26;27). In this role, BH4 competes with phenylalanine for binding to the regulatory domain to form a dead-end complex.
The C-terminal 42 amino acids comprise the tetramerization domain, and a PAH crystallizes as a tetramer (dimer of dimers) when this domain is present (11). The tetramerization domain contains two β-strands and an α-helix 40 Å in length (amino acids 428-452) that makes the coiled-coil interaction critical for tetramer formation (28). α-helices from four monomers pack into a tight antiparallel coiled-coil in the center of the tetramer.
The bronze mutation in leucine 242 is located at the center of the catalytic domain, within a β-strand approximately 8-10 Å from the active site iron atom. Leucine 242 is not part of the active site.
Northern blot analysis demonstrates that PAH transcript is most highly expressed in the liver, and at lower levels in the kidney, pancreas, and brain (29;30). Enzyme assay confirms PAH activity in the liver and kidney. In mice and rats, immunohistochemical analysis and enzyme assay identify Pah in the liver (hepatocytes) and at lower levels in the kidney (renal epithelial cells) (31;32). Low Pah activity is also detected in mouse pancreas (31;33) and rat brain (34). The expression of Pah in rodent liver is developmentally regulated such that it is first observed at low levels around embryonic days 17-18, and then dramatically upregulated within one week after birth (31;32). PAH is localized in the cytosol.
PAH catalyzes the hydroxylation of L-Phe to L-Tyr, the rate-limiting first step in the catabolic pathway leading to the complete oxidation of L-Phe to carbon dioxide and water. The catalytic mechanism of hydroxylation is believed to involve formation of a hydroxylating intermediate followed by oxygen transfer to the amino acid substrate (35). Kinetic and computational analyses support peroxy-pterin and Fe(IV)O-enzyme reaction intermediates, respectively, for each of these steps (1), however no intermediates have yet been captured for direct structural analysis, and thus the proposed reaction mechanism remains to be proven.
The catabolic pathway initiated by PAH in the liver and kidney accounts for at least 75% of the disposal of dietary phenylalanine. Deficiencies in the PAH pathway result in activation of the typically minor pathway for transamination of phenylalanine to phenylpyruvic acid, an α-keto acid. This and other metabolites of phenylalanine (phenyl lactate, phenylacetate, phenylethylamine, phenylacetyl glutamine) are excreted through the urine. Mutations in human PAH result in the recessively inherited disease hyperphenylalaninemia (high levels of phenylalanine in the blood). Severe forms of the disease are called phenylketonuria (PKU; OMIM #261600), first described in Norway in 1934 as “oligophrenica phenylpyruvica” [reviewed in (36;37)]. The essential feature of the disease was the urinary excretion of large amounts (about 1 gram per day) of phenylpyruvic acid, detected by adding a few drops of 5% ferric chloride solution to the urine and observing the development of a deep blue-green color. Mental retardation was almost always associated with the metabolic phenotype. The name phenylketonuria was proposed by Penrose in 1937 (38). In 1947, the metabolic defect was ascribed to an inability to oxidize phenylalanine to tyrosine (39), and in 1953, a deficiency in hepatic PAH activity was demonstrated in a patient (40). It was shown that the metabolic phenotype could be treated by dietary restriction of phenylalanine, with the potential to prevent mental retardation (41). To facilitate early detection, a blood test for PKU in newborns was developed in 1961 (42), and is now routinely administered to neonates in the United States and many other countries.
The pathologic changes in the brains of PKU patients are of two primary types (43). First, arrest or delay in the development of cortical neurons, and changes in the numbers of cortical neurons are thought to result in dysfunction of the late maturing regions of the neocortex. Mental retardation and seizures may be clinical manifestations of such defects. Similar findings have been reported in rodent models of PKU (44). White matter abnormalities such as spongy myelin, pale myelin staining, and demyelination are routinely observed (unlike cortical lesions) and constitute the second type of pathology observed in PKU brains. It has been hypothesized that elevated levels of phenylalanine are toxic to myelination (45). One proposed mechanism is that high levels of phenylalanine, through inhibition of the enzyme 3-hydroxyl-3methylglutaryl-coenzyme A reductase (HMGR; required for cholesterol biosynthesis), may prevent the production of myelin by oligodendrocytes (46-48). Cholesterol comprises 30% of myelin lipids and must be synthesized locally in the brain. Since myelin is critical to both axonal development and neurotransmission, an inability to produce or maintain myelin may lead to the neuronal dysfunction and mental retardation observed in PKU.
In addition to mental retardation, untreated classical PKU is characterized by an accentuation of all reflexes, epileptic seizures, and hyperkinetic behavior or spasticity (37;49). Physical characteristics include small stature, reduced head size, widely spaced incisor teeth, eczema, kyphosis, a ‘mousy’ odor, and sometimes excessive sweating. Light colored hair and eyes are also common due to impaired melanin production, which requires tyrosine (see record for ghost). Treatment involves restoration of blood phenylalanine levels to normal values as early in postnatal life and for as long as possible. The primary therapy is close monitoring of blood plasma L-Phe combined with dietary restriction of phenylalanine, found in high-protein foods such as milk, eggs, nuts, beans, chicken, beef, and fish. Dietary supplementation with phenylalanine-free formula may be used to provide essential nutrients required for development. However, even with early treatment, mildly depressed IQ is common in PKU (50). Some cases of PKU (~30% of classic PKU, and up to 70% of mild PKU), depending on the particular PAH allele, also respond to treatment with pharmacological doses of BH4 (51;52). A chaperone-like effect of BH4 on enzyme stability, increased binding of BH4 in the catalytic domain, and restoration of optimal concentrations of BH4 in hepatocytes may all contribute to the therapeutic effect (53;54).
The human gene encoding PAH was cloned in 1983 (55), and mutations in the gene are now known to account for 99% of all cases of hyperphenylalaninemia (HPA) (56). The remaining 1% result from mutations in genes encoding the enzymes responsible for BH4 biosynthesis. Extensive screening of newborns has revealed that a range of phenotypes exists, from the severe classical PKU to moderate PKU, mild PKU, and non-PKU HPA, for which the risk of impaired cognitive development is low. The prevalence of HPA (both PKU and non-PKU) is about 1 in 10,000 live births among European and Oriental Asian populations, while the incidence is less than 1 in 100,000 among sub-Saharan Africans and their descendants (57). Approximately 550 mutations in the PAH gene, identified by researchers internationally and reported in published articles or direct submissions, are currently recorded in the Phenylalanine Hydroxylase Locus Knowledgebase (PAHdb) (www.pahdb.mcgill.ca), although as few as six alleles account for 60% of all disease-causing alleles within certain ethnic populations. The majority are relatively rare alleles. Missense mutations are the most common type of mutation (61%).
To further study PAH in vivo, three ENU-induced Pah-deficient mouse strains were generated and found to recapitulate human HPA disease. All three mouse alleles are recessive. Pahenu1 (also known as Pahhph5) causes a relatively mild phenotype similar to non-PKU HPA, with only slightly elevated levels of phenylalanine in the blood, and a reduced ability to clear a 1 mg/g intraperitoneal phenylalanine challenge (clearance within 6 hours versus 2 hours in control mice) (58;59). The Pahenu1 mutation is a T to C transition at nucleotide 364 in exon 3, resulting in a valine to alanine substitution at amino acid 106 (60). Although the mutation is associated with reduced Pah protein levels, the conservative nature of the amino acid change apparently permits sufficient residual activity to prevent severe HPA. A second ENU-induced mutation, Pahenu2, causes a classical PKU phenotype with serum phenylalanine and urinary ketone concentrations elevated 15.4-fold and 15-40-fold, respectively, over those of wild type mice (58). Homozygous Pahenu2 mice also display hypopigmented fur, reduced head size, and behavioral abnormalities beginning at 2 weeks of age. The mutation is a T to C transition at nucleotide 835 in exon 7 (the most frequently mutated exon in human PAH), resulting in a phenylalanine to serine substitution at amino acid 263 (60). Pahenu2 protein is detectable in liver extracts from homozygous mutants, but retains no catalytic activity (58). The third mutant allele, Pahenu3, results in a phenotype similar to that of Pahenu2 mice (58). Pahenu3 is a T to G transversion in the splice donor site of Pah intron 11 (61). The mutation induces usage of two cryptic splice donor sites, one 5 bp upstream and one 5 bp downstream of the normal splice site, both resulting in coding frameshifts and premature termination. No protein is detected in liver extracts from Pahenu3 homozygotes. These three Pah-deficient strains continue to be used for studies of phenylalanine metabolism in vivo.
The human PAH mutation L242F has been reported in a single PKU patient among a group from West Germany and Bulgaria (68). The bulky phenylalanine residue may disrupt protein folding and lead to degradation. A similar situation likely occurs in bronze mice containing the L242P mutation. Leucine 242 exists in the middle of a β-strand, and substitution with proline is predicted to disrupt this secondary structure. Notably, a mutant PAHR243Q protein retains less than 10% of wild type activity when expressed in COS cells (69).
|Primers||Primers cannot be located by automatic search.|
Bronze genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
bronze (F): 5’-TGTGAGGTTACATGACCCAAAGCAG -3’
bronze (R): 5’- GGAGATGCTGAGATCACTTGGCTAC -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
bronze_seq(F): 5’- TGCAACCTGGTAATACTGATCC -3’
bronze_seq(R): 5’- CCAAATCCTTGGTTCACAGGATG -3’
The following sequence of 745 nucleotides (from Genbank genomic region NC_000076 for linear genomic sequence of Pah, sense strand) is amplified:
47941 catgacccaa agcagtaggg gggttgtagt ctctctggat ttaccataag gcttacaatt
48001 ctcaaccttc ctaatgctgc aacctggtaa tactgatcct catgttgtgg tgaccaccaa
48061 ccacaaaatt actttgttgc tactttataa ctgcaatttt gctattctta tgaatcataa
48121 catttgattt atttgatatg caggatatct aaggtgccac ccccttgggg agtcatacct
48181 cacaggttgt aaaccactta taaaaagcct tgagttttag gttcttttct gctttccagc
48241 ttgtactggt ttccgcctcc gtcctgttgc tggcttactg tcgtctcgag atttcttggg
48301 tggcctggcc ttccgagtct tccactgcac acagtacatt aggcatggat ctaagcccat
48361 gtacacacct gaaccgtaag tatcattctt cagctacccc tgccaaccac aatggatgct
48421 caaagaatgc tgatcaggct cattgcaggc tggtccccat gatccactgc ctgctttatt
48481 tgatcatagt cctaaaggaa actcatactc tgtgaatttt ctctgtccaa atagatgaaa
48541 tttggactca cagagctgga catcctgtga accaaggatt tggaactctt tgagtaccag
48601 gaaaagggat tccatcaagc tccaatgttc caaataggac aggaacaaga gtagccaagt
48661 gatctcagca tctcc
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is indicated in red.
1. Bassan, A., Blomberg, M. R., and Siegbahn, P. E. (2003) Mechanism of Dioxygen Cleavage in Tetrahydrobiopterin-Dependent Amino Acid Hydroxylases. Chemistry. 9, 106-115.
2. Dix, T. A., Bollag, G. E., Domanico, P. L., and Benkovic, S. J. (1985) Phenylalanine Hydroxylase: Absolute Configuration and Source of Oxygen of the 4a-Hydroxytetrahydropterin Species. Biochemistry. 24, 2955-2958.
3. KAUFMAN, S., BRIDGERS, W. F., EISENBERG, F., and FRIEDMAN, S. (1962) The Source of Oxygen in the Phenylalanine Hydroxylase and the Copamine-Beta-Hydroxylase Catalyzed Rections. Biochem. Biophys. Res. Commun. 9, 497-502.
4. Thony, B., Auerbach, G., and Blau, N. (2000) Tetrahydrobiopterin Biosynthesis, Regeneration and Functions. Biochem. J. 347 Pt 1, 1-16.
5. Martinez, A., Knappskog, P. M., Olafsdottir, S., Doskeland, A. P., Eiken, H. G., Svebak, R. M., Bozzini, M., Apold, J., and Flatmark, T. (1995) Expression of Recombinant Human Phenylalanine Hydroxylase as Fusion Protein in Escherichia Coli Circumvents Proteolytic Degradation by Host Cell Proteases. Isolation and Characterization of the Wild-Type Enzyme. Biochem. J. 306 ( Pt 2), 589-597.
6. Erlandsen, H., Patch, M. G., Gamez, A., Straub, M., and Stevens, R. C. (2003) Structural Studies on Phenylalanine Hydroxylase and Implications Toward Understanding and Treating Phenylketonuria. Pediatrics. 112, 1557-1565.
7. Andersen, O. A., Flatmark, T., and Hough, E. (2002) Crystal Structure of the Ternary Complex of the Catalytic Domain of Human Phenylalanine Hydroxylase with Tetrahydrobiopterin and 3-(2-Thienyl)-L-Alanine, and its Implications for the Mechanism of Catalysis and Substrate Activation. J. Mol. Biol. 320, 1095-1108.
8. Andersen, O. A., Flatmark, T., and Hough, E. (2001) High Resolution Crystal Structures of the Catalytic Domain of Human Phenylalanine Hydroxylase in its Catalytically Active Fe(II) Form and Binary Complex with Tetrahydrobiopterin. J. Mol. Biol. 314, 279-291.
9. Erlandsen, H., Bjorgo, E., Flatmark, T., and Stevens, R. C. (2000) Crystal Structure and Site-Specific Mutagenesis of Pterin-Bound Human Phenylalanine Hydroxylase. Biochemistry. 39, 2208-2217.
10. Kobe, B., Jennings, I. G., House, C. M., Michell, B. J., Goodwill, K. E., Santarsiero, B. D., Stevens, R. C., Cotton, R. G., and Kemp, B. E. (1999) Structural Basis of Autoregulation of Phenylalanine Hydroxylase. Nat. Struct. Biol. 6, 442-448.
11. Fusetti, F., Erlandsen, H., Flatmark, T., and Stevens, R. C. (1998) Structure of Tetrameric Human Phenylalanine Hydroxylase and its Implications for Phenylketonuria. J. Biol. Chem. 273, 16962-16967.
12. Erlandsen, H., Fusetti, F., Martinez, A., Hough, E., Flatmark, T., and Stevens, R. C. (1997) Crystal Structure of the Catalytic Domain of Human Phenylalanine Hydroxylase Reveals the Structural Basis for Phenylketonuria. Nat. Struct. Biol. 4, 995-1000.
13. Erlandsen, H., and Stevens, R. C. (1999) The Structural Basis of Phenylketonuria. Mol. Genet. Metab. 68, 103-125.
14. Wang, G. A., Gu, P., and Kaufman, S. (2001) Mutagenesis of the Regulatory Domain of Phenylalanine Hydroxylase. Proc. Natl. Acad. Sci. U. S. A. 98, 1537-1542.
15. Knappskog, P. M., Flatmark, T., Aarden, J. M., Haavik, J., and Martinez, A. (1996) Structure/function Relationships in Human Phenylalanine Hydroxylase. Effect of Terminal Deletions on the Oligomerization, Activation and Cooperativity of Substrate Binding to the Enzyme. Eur. J. Biochem. 242, 813-821.
16. Dickson, P. W., Jennings, I. G., and Cotton, R. G. (1994) Delineation of the Catalytic Core of Phenylalanine Hydroxylase and Identification of Glutamate 286 as a Critical Residue for Pterin Function. J. Biol. Chem. 269, 20369-20375.
17. Fisher, D. B., and Kaufman, S. (1973) The Stimulation of Rat Liver Phenylalanine Hydroxylase by Lysolecithin and -Chymotrypsin. J. Biol. Chem. 248, 4345-4353.
18. Donlon, J., and Kaufman, S. (1978) Glucagon Stimulation of Rat Hepatic Phenylalanine Hydroxylase through Phosphorylation in Vivo. J. Biol. Chem. 253, 6657-6659.
19. Milstien, S., Abita, J. P., Chang, N., and Kaufman, S. (1976) Hepatic Phenylalanine 4-Monooxygenase is a Phosphoprotein. Proc. Natl. Acad. Sci. U. S. A. 73, 1591-1593.
20. Abita, J. P., Milstien, S., Chang, N., and Kaufman, S. (1976) In Vitro Activation of Rat Liver Phenylalanine Hydroxylase by Phosphorylation. J. Biol. Chem. 251, 5310-5314.
21. Doskeland, A. P., Schworer, C. M., Doskeland, S. O., Chrisman, T. D., Soderling, T. R., Corbin, J. D., and Flatmark, T. (1984) Some Aspects of the Phosphorylation of Phenylalanine 4-Monooxygenase by a Calcium-Dependent and Calmodulin-Dependent Protein Kinase. Eur. J. Biochem. 145, 31-37.
22. Doskeland, A. P., Doskeland, S. O., Ogreid, D., and Flatmark, T. (1984) The Effect of Ligands of Phenylalanine 4-Monooxygenase on the cAMP-Dependent Phosphorylation of the Enzyme. J. Biol. Chem. 259, 11242-11248.
23. Gottschall, D. W., Dietrich, R. F., Benkovic, S. J., and Shiman, R. (1982) Phenylalanine Hydroxylase. Correlation of the Iron Content with Activity and the Preparation and Reconstitution of the Apoenzyme. J. Biol. Chem. 257, 845-849.
24. Wallick, D. E., Bloom, L. M., Gaffney, B. J., and Benkovic, S. J. (1984) Reductive Activation of Phenylalanine Hydroxylase and its Effect on the Redox State of the Non-Heme Iron. Biochemistry. 23, 1295-1302.
25. Gibbs, B. S., Wojchowski, D., and Benkovic, S. J. (1993) Expression of Rat Liver Phenylalanine Hydroxylase in Insect Cells and Site-Directed Mutagenesis of Putative Non-Heme Iron-Binding Sites. J. Biol. Chem. 268, 8046-8052.
26. Mitnaul, L. J., and Shiman, R. (1995) Coordinate Regulation of Tetrahydrobiopterin Turnover and Phenylalanine Hydroxylase Activity in Rat Liver Cells. Proc. Natl. Acad. Sci. U. S. A. 92, 885-889.
27. Xia, T., Gray, D. W., and Shiman, R. (1994) Regulation of Rat Liver Phenylalanine Hydroxylase. III. Control of Catalysis by (6R)-Tetrahydrobiopterin and Phenylalanine. J. Biol. Chem. 269, 24657-24665.
28. Lohse, D. L., and Fitzpatrick, P. F. (1993) Identification of the Intersubunit Binding Region in Rat Tyrosine Hydroxylase. Biochem. Biophys. Res. Commun. 197, 1543-1548.
29. Lichter-Konecki, U., Hipke, C. M., and Konecki, D. S. (1999) Human Phenylalanine Hydroxylase Gene Expression in Kidney and Other Nonhepatic Tissues. Mol. Genet. Metab. 67, 308-316.
30. Ayling, J. E., Pirson, W. D., al-Janabi, J. M., and Helfand, G. D. (1974) Kidney Phenylalanine Hydroxylase from Man and Rat. Comparison with the Liver Enzyme. Biochemistry. 13, 78-85.
31. Wang, Y., DeMayo, J. L., Hahn, T. M., Finegold, M. J., Konecki, D. S., Lichter-Konecki, U., and Woo, S. L. (1992) Tissue- and Development-Specific Expression of the Human Phenylalanine hydroxylase/chloramphenicol Acetyltransferase Fusion Gene in Transgenic Mice. J. Biol. Chem. 267, 15105-15110.
32. McGee, M. M., Greengard, O., and Knox, W. E. (1972) The Quantitative Determination of Phenylalanine Hydroxylase in Rat Tissues. its Developmental Formation in Liver. Biochem. J. 127, 669-674.
33. Tourian, A., Goddard, J., and Puck, T. T. (1969) Phenylalanine Hydroxylase Activity in Mammalian Cells. J. Cell. Physiol. 73, 159-170.
34. Wapnir, R. A., Hawkins, R. L., and Stevenson, J. H. (1971) Ontogenesis of Phenylalanine and Tryptophan Hydroxylation in Rat Brain and Liver. Biol. Neonate. 18, 85-93.
35. Fitzpatrick, P. F. (2003) Mechanism of Aromatic Amino Acid Hydroxylation. Biochemistry. 42, 14083-14091.
36. Scriver, C. R. (2007) The PAH Gene, Phenylketonuria, and a Paradigm Shift. Hum. Mutat. 28, 831-845.
38. Penrose, L., and Quastel, J. H. (1937) Metabolic Studies in Phenylketonuria. Biochem. J. 31, 266-274.
39. JERVIS, G. A. (1947) Studies on Phenylpyruvic Oligophrenia: The Position of the Metabolic Error. J Biol Chem. 169, 651-656.
40. JERVIS, G. A. (1953) Phenylpyruvic Oligophrenia Deficiency of Phenylalanine-Oxidizing System. Proc. Soc. Exp. Biol. Med. 82, 514-515.
42. GUTHRIE, R., and SUSI, A. (1963) A Simple Phenylalanine Method for Detecting Phenylketonuria in Large Populations of Newborn Infants. Pediatrics. 32, 338-343.
43. Huttenlocher, P. R. (2000) The Neuropathology of Phenylketonuria: Human and Animal Studies. Eur. J. Pediatr. 159 Suppl 2, S102-6.
44. Cordero, M. E., Trejo, M., Colombo, M., and Aranda, V. (1983) Histological Maturation of the Neocortex in Phenylketonuric Rats. Early Hum. Dev. 8, 157-173.
45. Bauman, M. L., and Kemper, T. L. (1982) Morphologic and Histoanatomic Observations of the Brain in Untreated Human Phenylketonuria. Acta Neuropathol. 58, 55-63.
46. Shefer, S., Tint, G. S., Jean-Guillaume, D., Daikhin, E., Kendler, A., Nguyen, L. B., Yudkoff, M., and Dyer, C. A. (2000) Is there a Relationship between 3-Hydroxy-3-Methylglutaryl Coenzyme a Reductase Activity and Forebrain Pathology in the PKU Mouse? J. Neurosci. Res. 61, 549-563.
47. Dyer, C. A. (2000) Comments on the Neuropathology of Phenylketonuria. Eur. J. Pediatr. 159 Suppl 2, S107-8.
48. Dyer, C. A., Kendler, A., Philibotte, T., Gardiner, P., Cruz, J., and Levy, H. L. (1996) Evidence for Central Nervous System Glial Cell Plasticity in Phenylketonuria. J. Neuropathol. Exp. Neurol. 55, 795-814.
49. PAINE, R. S. (1957) The Variability in Manifestations of Untreated Patients with Phenylketonuria (Phenylpyruvic Aciduria). Pediatrics. 20, 290-302.
50. Griffiths, P. V., Demellweek, C., Fay, N., Robinson, P. H., and Davidson, D. C. (2000) Wechsler Subscale IQ and Subtest Profile in Early Treated Phenylketonuria. Arch. Dis. Child. 82, 209-215.
51. Bernegger, C., and Blau, N. (2002) High Frequency of Tetrahydrobiopterin-Responsiveness among Hyperphenylalaninemias: A Study of 1,919 Patients Observed from 1988 to 2002. Mol. Genet. Metab. 77, 304-313.
52. Kure, S., Hou, D. C., Ohura, T., Iwamoto, H., Suzuki, S., Sugiyama, N., Sakamoto, O., Fujii, K., Matsubara, Y., and Narisawa, K. (1999) Tetrahydrobiopterin-Responsive Phenylalanine Hydroxylase Deficiency. J. Pediatr. 135, 375-378.
53. Kure, S., Sato, K., Fujii, K., Aoki, Y., Suzuki, Y., Kato, S., and Matsubara, Y. (2004) Wild-Type Phenylalanine Hydroxylase Activity is Enhanced by Tetrahydrobiopterin Supplementation in Vivo: An Implication for Therapeutic Basis of Tetrahydrobiopterin-Responsive Phenylalanine Hydroxylase Deficiency. Mol. Genet. Metab. 83, 150-156.
54. Blau, N., and Erlandsen, H. (2004) The Metabolic and Molecular Bases of Tetrahydrobiopterin-Responsive Phenylalanine Hydroxylase Deficiency. Mol. Genet. Metab. 82, 101-111.
55. Woo, S. L., Lidsky, A. S., Guttler, F., Chandra, T., and Robson, K. J. (1983) Cloned Human Phenylalanine Hydroxylase Gene Allows Prenatal Diagnosis and Carrier Detection of Classical Phenylketonuria. Nature. 306, 151-155.
56. Scriver, C. R., Levy, H., and Donlon, J. (2008) Hyperphenylalaninemia: Phenylalanine Hydroxylase Deficiency, in The Online Metabolic and Molecular Bases of Inherited Disease (D. Valle, A. L. Beaudet, B. Vogelstein, K. W. Kinzler, S. E. Antonarakis, and A. Ballabio, Eds.) pp online, McGraw-Hill, New York.
57. Scriver, C. R. (2006) Homeostasis, Complexity, and Monogenic Phenotypes: The View from Phenylketonuria, in The Online Metabolic and Molecular Bases of Inherited Disease (D. Valle, A. L. Beaudet, B. Vogelstein, K. W. Kinzler, S. E. Antonarakis, and A. Ballabio, Eds.) pp Online, McGraw-Hill, New York.
58. Shedlovsky, A., McDonald, J. D., Symula, D., and Dove, W. F. (1993) Mouse Models of Human Phenylketonuria. Genetics. 134, 1205-1210.
59. McDonald, J. D., Bode, V. C., Dove, W. F., and Shedlovsky, A. (1990) Pahhph-5: A Mouse Mutant Deficient in Phenylalanine Hydroxylase. Proc. Natl. Acad. Sci. U. S. A. 87, 1965-1967.
60. McDonald, J. D., and Charlton, C. K. (1997) Characterization of Mutations at the Mouse Phenylalanine Hydroxylase Locus. Genomics. 39, 402-405.
61. Haefele, M. J., White, G., and McDonald, J. D. (2001) Characterization of the Mouse Phenylalanine Hydroxylase Mutation Pah(enu3). Mol. Genet. Metab. 72, 27-30.
62. Kayaalp, E., Treacy, E., Waters, P. J., Byck, S., Nowacki, P., and Scriver, C. R. (1997) Human Phenylalanine Hydroxylase Mutations and Hyperphenylalaninemia Phenotypes: A Metanalysis of Genotype-Phenotype Correlations. Am. J. Hum. Genet. 61, 1309-1317.
63. Weiss, K. M., and Buchanan, A. V. (2003) Evolution by Phenotype: A Biomedical Perspective. Perspect. Biol. Med. 46, 159-182.
64. Waters, P. J. (2003) How PAH Gene Mutations Cause Hyper-Phenylalaninemia and Why Mechanism Matters: Insights from in Vitro Expression. Hum. Mutat. 21, 357-369.
65. Eiken, H. G., Knappskog, P. M., Apold, J., and Flatmark, T. (1996) PKU Mutation G46S is Associated with Increased Aggregation and Degradation of the Phenylalanine Hydroxylase Enzyme. Hum. Mutat. 7, 228-238.
66. Bjorgo, E., Knappskog, P. M., Martinez, A., Stevens, R. C., and Flatmark, T. (1998) Partial Characterization and Three-Dimensional-Structural Localization of Eight Mutations in Exon 7 of the Human Phenylalanine Hydroxylase Gene Associated with Phenylketonuria. Eur. J. Biochem. 257, 1-10.
67. Waters, P. J., Parniak, M. A., Hewson, A. S., and Scriver, C. R. (1998) Alterations in Protein Aggregation and Degradation due to Mild and Severe Missense Mutations (A104D, R157N) in the Human Phenylalanine Hydroxylase Gene (PAH). Hum. Mutat. 12, 344-354.
68. Dworniczak, B., Kalaydjieva, L., Pankoke, S., Aulehla-Scholz, C., Allen, G., and Horst, J. (1992) Analysis of Exon 7 of the Human Phenylalanine Hydroxylase Gene: A Mutation Hot Spot? Hum. Mutat. 1, 138-146.
|Science Writers||Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine|
|Authors||Owen M. Siggs, Bruce Beutler|
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