6 Molecular Genetics of Phenylketonuria: From Molecular Anthropology to Gene Therapy

Abadie, 1989, CpG dinucleotides are mutation hot spots in phenylketonuria, Genomics, 5, 936, 10.1016/0888-7543(89)90137-7 Abadie, 1993, Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria, Hum. Mol. Genet., 2, 31, 10.1093/hmg/2.1.31 Abadie, 1993, Molecular basis of phenylketonuria in France, Dev. Brain Dys., 6, 120 Abita, 1983, Phenylalanine hydroxylase. Evidence that the enzyme from human liver might not be a phosphoprotein, Biochem. Int., 7, 727 Abita, 1976, In vitro activation of rat liver phenylalanine hydroxylase by phosphorylation, J. Biol. Chem., 251, 5310, 10.1016/S0021-9258(17)33162-9 Akli, 1993, Transfer of a foreign gene into the brain using adenovirus vectors, Nature Genet., 3, 224, 10.1038/ng0393-224 Aoki, 1988, Outcome of the patients detected by newborn screening in Japan, Acta Paediatr., 30, 429, 10.1111/j.1442-200X.1988.tb02533.x Apold, 1990, A termination mutation prevalent in Norwegian haplotype 7 phenylketonuria genes, Am. J. Hum. Genet., 47, 1002 Apold, 1993, The phenylketonuria G272X haplotype 7 mutation in European populations, Hum. Genet., 92, 107, 10.1007/BF00219674 Armstrong, 1956, Studies on phenylketonuria. V. Observations on a newborn infant with phenylketonuria, Proc. Soc. Exp. Biol. Med., 93, 418, 10.3181/00379727-93-22775 Armstrong, 1957, Studies on phenylketonuria. VIII. Relation between age, serum phenylalanine level and phenylpyruvic acid excretion, Proc. Soc. Exp. Biol. Med., 94, 142, 10.3181/00379727-94-22880 Armstrong, 1955, Studies on phenylketonuria. I. Restricted phenylalanine intake in phenylketonuria, J. Clin. Invest., 34, 565, 10.1172/JCI103105 Aulehla-Scholz, 1988, Phenylketonuria: Distribution of DNA diagnostic patterns in German families, Hum. Genet., 78, 353, 10.1007/BF00291734 Avigad, 1990, A single origin of phenylketonuria in Yemenite Jews, Nature, 344, 168, 10.1038/344168a0 Avigad, 1991, Compound heterozygosity in nonphenylketonuria hyperphenylalaninemia: The contribution of mutations for classical phenylketonuria, Am. J. Hum. Genet., 49, 393 Ayling, 1974, Kidney phenylalanine hydroxylase from man and rat: Comparison with the liver enzyme, Biochemistry, 13, 78, 10.1021/bi00698a013 Bajocchi, 1993, Direct in vivo gene transfer to ependymal cells in the central nervous system using recombinant adenovirus vectors, Nature Genet., 3, 229, 10.1038/ng0393-229 Baric, 1992, Haplotype distributions and mutations at the PAH locus in Croatia, Hum. Genet., 90, 155, 10.1007/BF00210763 Bartholomé, 1982, Studies on the molecular defect in phenylketonuria and hyperphenylalaninemia using antibodies against phenylalanine hydroxylase, J. Inherited Metab. Dis., 5, 7, 10.1007/BF01799747 Bartholomé, 1975, Determination of phenylalanine hydroxylase activity in patients with phenylketonuria and hyperphenylalaninemia, Pediatr. Res., 9, 899, 10.1203/00006450-197512000-00006 Benit, 1994, Novel frame shift deletions of the phenylalanine hydroxylase gene in phenylketonuria, Hum. Mol. Genet., 3, 675, 10.1093/hmg/3.4.675 Berk, 1974, A linkage study of phenylketonuria, Clin. Genet., 6, 147, 10.1111/j.1399-0004.1974.tb00644.x Berthelon, 1991, Spectrum of phenylketonuria mutations in Western Europe and North Africa, and their relation to polymorphic DNA haplotypes at the phenylalanine hydroxylase locus, Hum. Genet., 86, 355, 10.1007/BF00201832 Bick, 1991, Disturbed myelination in patients with treated hyperphenylalaninemia: Evaluation with magnetic resonance imaging, Eur. J. Pediatr., 150, 185, 10.1007/BF01963563 Bickel, 1954, The influence of phenylalanine intake on the chemistry and behavior of a phenylketonuria child, Acta Paediatr. Scand., 43, 64, 10.1111/j.1651-2227.1954.tb04000.x Bickel, 1981, Neonatal mass screening for metabolic disorders, Eur. J. Pediatr., 137, 133 Blaskovics, 1988, A new variant of biopterin deficiency, N. Engl. J. Med., 319, 1611, 10.1056/NEJM198812153192420 Bosco, 1991, Identification of a new PKU mutation (R261 ter) by SSCP analysis, Clin. Genet., 40, 392 Boyd, 1961, Phenylketonuria; City of Birmingham screening survey, Br. Med. J., 1, 771, 10.1136/bmj.1.5228.771 Byck, 1992, Extended RFLP and HindIII specific haplotypes at the PAH (PKU) locus on chromosomes in France and Québec, Am. J. Hum. Genet., 51, A571 Caillaud, 1991, A 3-base pair in-frame deletion of the phenylalanine hydroxylase gene results in a kinetic variant of phenylketonuria, J. Biol. Chem., 266, 9351, 10.1016/S0021-9258(18)92824-3 Caillaud, 1992, Linkage disequilibrium between phenylketonuria and RFLP haplotype 1 at the phenylalanine hydroxylase locus in Portugal, Hum. Genet., 89, 69, 10.1007/BF00207045 Campbell, 1986, Identification of four phosphorylation sites in the N-terminal region of tyrosine hydroxylase, J. Biol. Chem., 261, 10489, 10.1016/S0021-9258(18)67410-1 Centerwall, 1957, Phenylketonuria, J. Am. Med. Assoc., 165, 392, 10.1001/jama.1957.02980220076022 Chakraborty, 1987, Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria, Hum. Genet., 76, 40, 10.1007/BF00283048 Chen, 1989, Study of restriction fragment length polymorphisms at the human phenylalanine hydroxylase locus and evaluation of its potential application in prenatal diagnosis of phenylketonuria, Hum. Genet., 81, 226, 10.1007/BF00278993 Choo, 1979, Genetics of the mammalian phenylalanine hydroxylase system. Studies of human liver phenylalanine hydroxylase subunit structure and of mutations in phenylketonuria, Biochem. J., 181, 285, 10.1042/bj1810285 Choo, 1980, Observations indicating the nature of the mutation in phenylketonuria, J. Inherited Metab. Dis., 2, 79, 10.1007/BF01805662 Chowdhury, 1993, Fate of DNA targeted to the liver by asialoglycoprotein receptor-mediated endocytosis, In vivo. J. Biol. Chem., 268, 11265, 10.1016/S0021-9258(18)82119-6 Cooper, 1988, The CpG dinucleotide and human genetic disease, Hum. Genet., 78, 151, 10.1007/BF00278187 Cotten, 1992, High-efficiency receptor-mediated delivery of small and large (48 kilobase) gene constructs using the endosome-disruption activity of defective or chemically inactivated adenovirus particles, Proc. Natl. Acad. Sci. USA, 89, 6094, 10.1073/pnas.89.13.6094 Crawfurd, 1981, Studies on human phenylalanine mono-oxygenase: Restricted expression, J. Inherited Metab. Dis., 4, 191, 10.1007/BF02263650 Cristiano, 1993, Hepatic gene therapy: efficient gene delivery and expression in primary hepatocytes utilizing a conjugated adenovirus/DNA complex, Proc. Natl. Acad. Sci. USA, 90, 11548, 10.1073/pnas.90.24.11548 Cristiano, 1993, Hepatic gene therapy: Adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes, Proc. Natl. Acad. Sci. USA, 90, 2122, 10.1073/pnas.90.6.2122 Curiel, 1992, Gene transfer to respiratory epithelial cells via the receptor-mediated endocytosis pathway, Am. J. Respir. Cell. Mol. Biol., 6, 247, 10.1165/ajrcmb/6.3.247 Curiel, 1991, Adenovirus enhancement of transferrin/polylysine-mediated gene delivery, Proc. Natl. Acad. Sci. USA, 88, 8850, 10.1073/pnas.88.19.8850 Dahl, 1986, Isolation and sequence of a cDNA clone which contains the complete coding region of rat phenylalanine hydroxylase. Structural homology with tyrosine hydroxylase, glucocorticoid regulation, and use of alternate polyadenylation sites, J. Biol. Chem., 261, 4148, 10.1016/S0021-9258(17)35638-7 Daiger, 1986, Effective use of polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in prenatal diagnosis of phenylketonuria, Lancet, 1, 229, 10.1016/S0140-6736(86)90771-3 Daiger, 1989, Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in European families with phenylketonuria (PKU), Am. J. Hum. Genet., 45, 310 Daiger, 1989, Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in Asian families with phenylketonuria (PKU), Am. J. Hum. Genet., 45, 319 Dasovich, 1991, Molecular characterization of a PKU allele prevalent in Southern Europe and Ireland, Som. Cell. Mol. Genet., 17, 303, 10.1007/BF01232824 Davidson, 1993, A model system for in vivo gene transfer into the central nervous system using an adenoviral vector, Nature Genet., 3, 219, 10.1038/ng0393-219 Desviat, 1993, Phenylketonuria in Spain: RFLP haplotypes and linked mutations, Hum. Genet., 92, 254, 10.1007/BF00244468 Dhondt, 1985, Neonatal hyperphenylalaninemia presumably caused by guanosine triphosphatecyclohydrolase activity, J. Pediatr., 106, 954, 10.1016/S0022-3476(85)80251-1 Dhondt, 1988, Neonatal hyperphenylalaninemia presumably caused by a new variant of biopterin synthetase deficiency, Eur. J. Pediatr., 147, 153, 10.1007/BF00442213 Dianzani, 1992, Molecular analysis of phenylketonuria in Italy, Am. J. Hum. Genet., 51, A1374 Dianzani, 1990, Haplotype distribution and molecular defects at the phenylalanine hydroxylase locus in Italy, Hum. Genet., 86, 69, 10.1007/BF00205176 Dianzani, 1991, Screening for mutations in the phenylalanine hydroxylase gene from Italian patients with phenylketonuria by using the chemical cleavage method: A new splice mutation, Am. J. Hum. Genet., 48, 631 DiLella, 1988, Screening for phenylketonuria mutations by DNA amplification with the polymerase chain reaction, Lancet, 1, 497, 10.1016/S0140-6736(88)91295-0 DiLella, 1987, An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2, Nature, 327, 333, 10.1038/327333a0 DiLella, 1986, Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene, Biochemistry, 25, 743, 10.1021/bi00352a001 DiLella, 1986, Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria, Nature, 322, 799, 10.1038/322799a0 DiLella, 1985, Detection of phenylalanine hydroxylase messenger RNA in liver biopsy samples from patients with phenylketonuria, Lancet, 1, 160, 10.1016/S0140-6736(85)91925-7 DiSilvestre, 1991, Different clinical manifestations in three siblings with identical phenylalanine hydroxylase genes, Am. J. Hum. Genet., 48, 1014 Donlon, 1978, Glucagon stimulation of rat hepatic phenylalanine hydroxylase through phosphorylation in vivo, J. Biol. Chem., 253, 6657, 10.1016/S0021-9258(17)37966-8 Dworniczak, 1989, Phenylketonuria: Detection of a frequent haplotype 4 allele mutation, Hum. Genet., 84, 95, 10.1007/BF00210683 Dworniczak, 1991, Aberrant splicing of phenylalanine hydroxylase mRNA: The major cause for phenylketonuria in parts of Southern Europe, Genomics, 11, 242, 10.1016/0888-7543(91)90129-3 Dworniczak, 1991, Phenylalanine hydroxylase gene: Novel missense mutation in exon 7 causing severe phenylketonuria, Genomics, 9, 193, 10.1016/0888-7543(91)90238-A Dworniczak, 1991, Recurrent nonsense mutation in exon 7 of the phenylalanine hydroxylase gene, Hum. Genet., 87, 731, 10.1007/BF00201735 Dworniczak, 1991, PCR detection of the Pvull (Ea) RFLP at the human phenylalanine hydroxylase (PAH) locus, Nucleic Acids Res., 19, 1958 Dworniczak, 1991, PCR detection of the BgIII RFLP at the human phenylalanine hydroxylase (PAH) locus, Nucleic Acids Res., 19, 1958 Dworniczak, 1992, Analysis of exon 7 of the human phenylalanine hydroxylase gene: A mutation hot spot?, Hum. Mutot., 1, 138, 10.1002/humu.1380010209 Economou-Petersen, 1992, Molecular basis for nonphenylketonuria hyperphenylalaninemia, Genomics, 14, 1, 10.1016/S0888-7543(05)80274-5 Eigel, 1991, A frameshift mutation in exon 2 of the phenylalanine hydroxylase gene linked to RFLP haplotype 1, Hum. Genet., 87, 739, 10.1007/BF00201738 Eiken, 1992, A de novo phenylketonuria mutation: ATG (Met) to ATA (He) in the start codon of the phenylalanine hydroxylase gene, Hum Mutat., 1, 388, 10.1002/humu.1380010507 Eiken, 1992, PKU mutations R408Q and F299C in Norway: Haplotype associations, geographical distributions and phenotype characteristics, Hum. Genet., 88, 608, 10.1007/BF02265283 Eiken, 1993, Prevalence and geographic distribution of PKU mutations in Norway, 25Th Annu. Meeting Eur. Soc. Hum. Gene., A211 Eisensmith, 1991, Phenylketonuria and the phenylalanine hydroxylase gene, Mol. Biol. Med., 8, 3 Eisensmith, 1992, Molecular basis of phenylketonuria and related hyperphenylalaninemias: Mutations and polymorphisms in the human phenylalanine hydroxylase gene, Hum. Mutat., 1, 13, 10.1002/humu.1380010104 Eisensmith, 1992, Undated listing of haplotypes at the human phenylalanine hydroxylase (PAH) locus, Am. J. Hum. Genet., 51, 1445 Eisensmith, 1994, A simple, rapid, and highly informative PCR-based procedure for prenatal diagnosis and carrier screening of phenylketonuria, Prenatal Diag., 10.1002/pd.1970141204 Eisensmith, 1992, Multiple origins for phenylketonuria in Europe, Am. J. Hum. Genet., 51, 1355 Eisensmith, 1991, Molecular basic of phenylketonuria (PKU), Am. J. Hum. Genet., 49, A455 1990, Gradient of distribution in Europe of the major CF mutation and of its associated haplotype, Hum. Genet., 85, 436, 10.1007/BF02428304 Fang, 1994, Gene therapy for phenylketonuria: Phenotypic correction in a genetically deficient mouse model by adenovirus-mediated hepatic gene transfer, Gene Ther., 1, 241 Ferry, 1991, Retroviral-mediated gene transfer into hepatocytes in vivo., Proc. Natl. Acad. Sci. USA, 88, 8377, 10.1073/pnas.88.19.8377 Foiling, 1934, Utskillelse av fenylpyrodruesyre i urinen som stoffskifteanomali i forbindelse med imbecillitet, Nord. Med. Tidskr., 8, 1054 Fölling, 1934, Über Ausscheidung von Phenylbrenztraubensaure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität, Ztschr. Physiol. Chem., 227, 169, 10.1515/bchm2.1934.227.1-4.169 Forrest, 1991, Mutation detection in phenylketonuria using chemical cleavage of mismatch: Importance of using probes from both normal and patient samples, Am. J. Hum. Genet., 49, 175 Friedman, 1973, Some characteristics of partially purified human liver phenylalanine hydroxylase, Biochim. Biophys. Acta, 293, 56, 10.1016/0005-2744(73)90375-6 Garrod, 1908, Inborn errors of metabolism, Lancet, 2, 1, 10.1016/S0140-6736(01)78482-6 Gibbs, 1959, Tests for phenylketonuria: Results of a one-year programme for its detection in infancy and among mental defectives, Br. Med. J., 2, 532, 10.1136/bmj.2.5151.532 Gilardi, 1990, Expression of human alpha-1-antitrypsin using a recombinant adenovirus vector, FEBS Lett., 267, 60, 10.1016/0014-5793(90)80287-S Goebel-Schreiner, 1993, Identification of a new missense mutation in Japanese phenylketonuric patients, J. Inher. Metab. Dis., 16, 950, 10.1007/BF00711510 Gold, 1974, The use of biochemical data in screening for mutant alleles and in genetic counseling, Ann. Hum. Genet., 37, 315, 10.1111/j.1469-1809.1974.tb01838.x Goldstein, 1985, Receptor-mediated endocytosis: Concepts emerging from the LDL receptor system, Annu. Rev. Cell Biol., 1, 1, 10.1146/annurev.cb.01.110185.000245 Goltsov, 1992, Linkage disequilibrium between mutations and a VNTR in the human phenylalanine hydroxylase gene, Am. J. Hum. Genet., 51, 627 Goltsov, 1992, Detection of the XmnI RFLP at the human phenylalanine hydroxylase locus by PCR, Nucleic Acids Res., 20, 927, 10.1093/nar/20.4.927-a Goltsov, 1993, A single polymorphic STR system in the human phenylalanine hydroxylase gene permits rapid prenatal diagnosis and carrier screening for phenylketonuria, Hum. Mol. Genet., 2, 577, 10.1093/hmg/2.5.577 Gottschalk, 1994, Folare-mediated DNA delivery into tumor cells: Potosomal disruption results in enhanced gene expression, Gene Ther., 1, 185 Gregory, 1986, Plasma free amino acid values in normal children and adolescents, Metabolism, 35, 967, 10.1016/0026-0495(86)90063-6 Grenett, 1987, Full-length cDNA for rabbit tryptophan hydroxylase: Functional domains and evolution of aromatic amino acid hydroxylases, Proc. Natl. Acad. Sci. USA, 4, 5530, 10.1073/pnas.84.16.5530 Grossman, 1994, Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolemia, Nature Genet., 6, 335, 10.1038/ng0494-335 Guldberg, 1993, A simple method for identification of point mutations using denaturing gradient gel electrophoresis, Nucleic Acids Res., 21, 2261, 10.1093/nar/21.9.2261 Guldberg, 1993, Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis, Genomics, 17, 141, 10.1006/geno.1993.1295 Guldberg, 1993, A novel missense mutation in the phenylalanine hydroxylase gene of a homozygous Pakistani patient with non-PKU hyperphenylalaninemia, Hum. Mol. Genet., 2, 1061, 10.1093/hmg/2.7.1061 Guldberg, 1993, Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: Implications for diagnosis of hyperphenylalaninemia in Southern Europe, Hum. Mol. Genet., 2, 1703, 10.1093/hmg/2.10.1703 Gupta, 1991, Permanent engraftment and function of hepatocytes delivered to the liver: Implications for gene therapy and liver repopulation, Hepatology, 14, 144, 10.1002/hep.1840140124 Guthrie, 1961, Blood screening for phenylketonuria, JAMA, 178, 863, 10.1001/jama.1961.03040470079019 Guthrie, 1963, A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants, Pediatrics, 32, 338 Güttler, 1980, Hyperphenylalaninemia: Diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood, Acta Paediatr. Scand., 280, 1 Güttler, 1993, Mutation genotype of mentally retarded patients with phenylketonuria, Dev. Brain Dys., 6, 92 Guttler, 1993, Molecular basis for the phenotypical diversity of phenylketonuria and related hyper-phenylalaninemias, J. Inher. Metab. Dis., 16, 602, 10.1007/BF00711693 Güttler, 1987, Correlation between polymorphic DNA haplotypes at phenylalanine hydroxylase locus and clinical phenotypes of phenylketonuria, J. Pediatr., 110, 68, 10.1016/S0022-3476(87)80290-1 Haan, 1987, Identification of serotonergic neurons in human brain by a monoclonal antibody binding to all three aromatic amino acid hydroxylases, Brain Res., 426, 19, 10.1016/0006-8993(87)90420-3 Herrmann, 1988, Haplotype analysis of classical and mild phenotype of phenylketonuria in the German Democratic Republic, Clin. Genet., 34, 176, 10.1111/j.1399-0004.1988.tb02859.x Hertzberg, 1989, Phenylalanine hydroxylase gene haplotypes in Polynesians: Evolutionary origins and absence of alleles associated with severe phenylketonuria, Am. J. Hum. Genet., 44, 382 Herz, 1993, Adenovirus-mediated transfer of low density lipoprotein receptor gene acutely accelerates cholesterol clearance in normal mice, Proc. Natl. Acad. Sci. USA, 90, 2812, 10.1073/pnas.90.7.2812 Hoeben, 1992, Gene therapy for human inherited disorders: Techniques and status, Crit. Rev. Oncol., 13, 33, 10.1016/1040-8428(92)90015-I Hofman, 1989, Phenylketonuria in the Greek population, Mol. Biol. Med., 6, 245 Hofman, 1991, Phenylketonuria in U.S. blacks: Molecular analysis of the phenylalanine hydroxylase gene, Am. J. Hum. Genet., 48, 791 Hommes, 1993, The effect of hyperphenylalaninemia on the muscarinic acetylcholine receptor in the HPH-5 mouse brain, J. Inherited Metab. Dis., 16, 962, 10.1007/BF00711512 Horst, 1991, Molecular basis of phenylketonuria: Report of an extensive study of various Caucasian populations, Am. J. Hum. Genet., 49, A2302 Horst, 1993, Phenylketonuria in Germany—Molecular heterogeneity and diagnostic implications, Dev. Brain Dys., 6, 32 Huang, 1990, Application of a new DNA sequence polymorphism as a genetic marker in prenatal diagnosis of phenylketonuria, J. Med. Genet., 27, 65, 10.1136/jmg.27.1.65 Ishibashi, 1993, Hypercholesterolemia in LDL receptor knockout mice and its reversal by adenovirus-mediated gene delivery, J. Clin. Invest, 92, 883, 10.1172/JCI116663 Iwaki, 1986, Proteolytic modification of the amino-terminal and carboxyl-terminal regions of rat hepatic phenylalanine hydroxylase, J. Biol. Chem., 261, 2051, 10.1016/S0021-9258(17)35895-7 Jaffe, 1992, Adenovirus-mediated in vivo gene transfer and expression in normal rat liver, Nature Genet., 1, 372, 10.1038/ng0892-372 Jaruzelska, 1992, Illegitimate transcription and in vitro splicing of PAH mRNA in a PKU patient carrying an intron point mutation that causes skipping of exon 11, Am. J. Hum. Genet., 51, A1385 Jaruzelska, 1993, Genetic background of clinical heterogeneity of phenylketonuria in Poland, J. Med. Genet., 30, 232, 10.1136/jmg.30.3.232 Jaruzelska, 1993, A new 15 bp deletion in exon 11 of the phenylalanine hydroxylase gene in phenylketonuria, Hum. Mol. Genet., 1, 763, 10.1093/hmg/1.9.763 Jennings, 1990, Structural similarities among enzyme pterin binding sites as demonstrated by a monoclonal anti-idiotypic antibody, J. Biol. Chem., 265, 1885, 10.1016/S0021-9258(19)39913-2 Jennings, 1991, Localization of cofactor binding sites with monoclonal anti-idiotype antibodies: Phenylalanine hydroxylase, Proc. Natl. Acad. Sci. USA, 88, 5734, 10.1073/pnas.88.13.5734 Jervis, 1939, The genetics of phenylpyruvic oligophrenia. (A contribution to the study of the influence of heredity on mental defect.), J. Ment. Sci. (London), 85, 719, 10.1192/bjp.85.357.719 Jervis, 1947, Studies on phenylpyruvic oligophrenia. The position of the metabolic error, J. Biol. Chem., 169, 651, 10.1016/S0021-9258(17)30882-7 Jervis, 1953, Phenylpyruvic oligophrenia deficiency of phenylalanine-oxidizing system, Proc. Soc. Exp. Biol. Med., 82, 514 Jervis, 1954, Phenylpyruvic oligophrenia (phenylketonuria), A. Res. Nerv. Ment. Dis., 35, 259 Jervis, 1940, Phenylalanine content of blood and spinal fluid in phenylpyruvic oligophrenia, J. Biol. Chem., 134, 105, 10.1016/S0021-9258(18)73252-3 John, S. W. M. (1991). Haplotypes and mutations at the phenylalanine hydroxylase locus in French Canadians. Thesis, McGill University, Montreal, Canada. John, 1988, RFLP haplotypes associated with hyperphenylalaninemia alleles at the phenylalanine hydroxylase (PAH) locus in French-Canadians, Am. J. Hum. Genet., 43 John, 1989, Novel PKU mutation on haplotype 2 in French-Canadians, Am. J. Hum. Genet., 45, 905 John, 1990, Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: Evidence in French-Canadians and a catalog of mutations, Am. J. Hum. Genet., 46, 970 John, 1992, In vitro and in vivo correlations for the 165T and M1V mutations at the phenylalanine hydroxylase locus, Hum. Mutat., 1, 147, 10.1002/humu.1380010210 Kalaydjieva, 1990, Classical phenylketonuria in Bulgaria: RFLP haplotypes and frequency of the major mutations, J. Med. Genet., 27, 742, 10.1136/jmg.27.12.742 Kalaydjieva, 1991, Phenylketonuria mutation in southern Europeans, Lancet, 337, 865, 10.1016/0140-6736(91)92584-O Kalaydjieva, 1991, Silent mutations in the phenylalanine hydroxylase gene as an aid to the diagnosis of phenylketonuria, J. Med. Genet., 28, 686, 10.1136/jmg.28.10.686 Kalaydjieva, 1991, Geographical distribution gradients of the major PKU mutations and the linked haplotypes, Hum. Genet., 86, 411, 10.1007/BF00201847 Kalaydjieva, 1992, Heterogeneity of mutations in Bulgarian phenylketonuria haplotype 1 and 4 alleles, Clin. Genet., 41, 123, 10.1111/j.1399-0004.1992.tb03647.x Kalaydjieva, 1993, Population genetics of phenylketonuria in Bulgaria, Dev. Brain Dys., 6, 39 Kaleko, 1991, Persistent gene expression after retroviral gene transfer into liver cells, In vivo. Hum. Gene Ther., 2, 27, 10.1089/hum.1991.2.1-27 Kamaryt, 1978, PKU locus: Genetic linkage with human amylase (Amy) loci and assignment to linkage group I, Hum. Genet., 43, 205, 10.1007/BF00293596 Kang, 1970, Clinical and biochemical observations of patients with atypical phenylketonuria, Pediatrics, 45, 83 Kaufman, 1958, A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine, J. Biol. Chem., 230, 931, 10.1016/S0021-9258(18)70516-4 Kaufman, 1958, Phenylalanine hydroxylation cofactor in phenylketonuria, Science, 128, 1506, 10.1126/science.128.3337.1506 Kaufman, 1959, Studies on the mechanism of the enzymatic conversion of phenylalanine to tyrosine, J. Biol. Chem., 234, 2677, 10.1016/S0021-9258(18)69758-3 Kaufman, 1963, The structure of the phenylalanine-hydroxylation cofactor, Proc. Natl. Acad. Sci. USA, 50, 1085, 10.1073/pnas.50.6.1085 Kaufman, 1970, A protein that stimulates rat liver phenylalanine hydroxylase, J. Biol. Chem., 245, 4751, 10.1016/S0021-9258(18)62857-1 Kaufman, 1978, Hyperphenylalaninemia due to a deficiency of biopterin. A variant form of phenylketonuria, N. Engl. J. Med, 299, 673, 10.1056/NEJM197809282991301 Kaufman, 1975, Phenylketonuria due to a deficiency of dihydropteridine reductase, N. Engl. J. Med., 293, 785, 10.1056/NEJM197510162931601 Kaufman, 1975, Phenylalanine hydroxylase activity in liver biopsies from hyperphenylalaninemia heterozygotes: Deviation from proportionality with gene dosage, Pediatr. Res., 9, 632, 10.1203/00006450-197508000-00004 Kay, 1992, Expression of human α1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes, Proc. Natl. Acad. Sci. USA, 89, 89, 10.1073/pnas.89.1.89 Kay, 1992, Hepatic gene therapy: Persistent expression of human α1-antitrypsin in mice after direct gene delivery in vivo, Hum. Gene Ther., 3, 641, 10.1089/hum.1992.3.6-641 Kay, 1993, In vivo gene therapy of hemophilia B: Sustained partial correction in factor IX deficient dogs, Science, 262, 117, 10.1126/science.8211118 Kleiman, 1991, A defective splice site at the phenylalanine hydroxylase gene in phenylketonuria and benign hyperphenylalaninemia among Palestinian Arabs, Hum. Mutat., 1, 340, 10.1002/humu.1380010413 Kleiman, 1992, A 22-bp deletion in the phenylalanine hydroxylase gene causing phenylketonuria in an Arab family, Hum. Mutat., 1, 344, 10.1002/humu.1380010414 Kleiman, 1993, Inactivation of phenylalanine hydroxylase by a missense mutation, R270S, in a Palestinian kinship with phenylketonuria, Hum. Mol. Genet., 2, 605, 10.1093/hmg/2.5.605 Koch, 1984, Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age, J. Inher. Metab. Dis., 7, 86, 10.1007/BF01805813 Konecki, 1991, The identification of two mis-sense mutations at the PAH gene in a Turkish patient with phenylketonuria, Hum. Genet., 87, 389, 10.1007/BF00197153 Kotake, 1922, Über das Verhalten des Phenylalanins im tierischen Organismus, Ztschr. Physiol. Chem., 122, 195, 10.1515/bchm2.1922.122.4-6.195 Kwok, 1985, Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase, Biochemistry, 24, 556, 10.1021/bi00324a002 Labrune, 1991, Single-strand conformation polymorphism for detection of mutations and base substitutions in phenylketonuria, Am. J. Hum. Genet., 48, 1115 Langenbeck, 1988, Correlative study of mental and biochemical phenotypes in never treated patients with classical phenylketonuria, Brain Dys., 1, 103 Lazarus, 1983, Phenylalanine hydroxylase stimulator protein is a 4α-carbinolamine dehydratase, J. Biol. Chem., 258, 10960, 10.1016/S0021-9258(17)44370-5 Le Salle Gal La, 1993, An adenovirus vector for gene transfer into neurons and glia in the brain, Science, 259, 988, 10.1126/science.8382374 Leamon, 1991, Delivery of macromolecules into living cells: A method that exploits folate receptor endocytosis, Proc. Natl. Acad. Sci. USA, 88, 5572, 10.1073/pnas.88.13.5572 Leamon, 1993, Cytoxicity of momordin-folate conjugates in cultured human cells, J. Biol. Chem., 267, 24966, 10.1016/S0021-9258(19)73992-1 Leandro, 1993, Sequencing analysis of PAH genomic DNA reveals 4 novel mutations affecting exons 7 and 11 in a Portugese PKU population, Abstr. SSIEM, Manchester. Ledley, 1985, Homology between phenylalanine hydroxylase and tyrosine hydroxylase reveals common structural and functional determinants, Biochemistry, 24, 3389, 10.1021/bi00335a001 Ledley, 1985, Gene transfer and expression of human phenylalanine hydroxylase, Science, 228, 77, 10.1126/science.3856322 Ledley, 1986, Retroviral-mediated gene transfer of human phenylalanine hydroxylase into NIH 3T3 and hepatoma cells, Proc. Natl. Acad. Sci. USA, 83, 409, 10.1073/pnas.83.2.409 Ledley, 1986, Molecular analysis of the inheritance of phenylketonuria and mild hyperphenylalaninemia in families with both disorders, N. Engl. J. Med., 314, 1276, 10.1056/NEJM198605153142002 Lenke, 1980, Maternal phenylketonuria and hyperphenylalaninemia: An international survey of the outcome of untreated and treated pregnancies, N. Engl. J. Med., 303, 1202, 10.1056/NEJM198011203032104 Levrero, 1991, Defective and nondefective adenovirus vectors for expressing foreign genes in vitro and in vivo, Gene, 101, 195, 10.1016/0378-1119(91)90411-4 Li, 1992, Identification of three novel missense PKU mutations among Chinese, Genomics, 13, 894, 10.1016/0888-7543(92)90180-Z Li, 1994, Phenylketonuria in China: Characterization of three novel mutations in the human phenylalanine hydroxylase gene, Hum. Mutat., 3, 312, 10.1002/humu.1380030323 Li, 1993, Assessment of recombinant adenoviral vectors for hepatic gene therapy, Hum. Gene Ther., 4, 403, 10.1089/hum.1993.4.4-403 Lichter-Konecki, 1988, Phenylalanine hydroxylase deficiency caused by a single base substitution in an exon of the human phenylalanine hydroxylase gene, Biochemistry, 27, 2881, 10.1021/bi00408a032 Lichter-Konecki, 1988, Linkage disequilibrium between mutation and RFLP haplotype at the phenylalanine hydroxylase locus in the German population, Hum. Genet., 78, 347, 10.1007/BF00291733 Lichter-Konecki, 1989, DNA haplotype analysis at the phenylalanine hydroxylase locus in the Turkish population, Hum. Genet., 81, 373, 10.1007/BF00283695 Lidsky, 1985, Prenatal diagnosis of classical phenylketonuria by DNA analysis, Lancet, 1, 549, 10.1016/S0140-6736(85)91208-5 Lidsky, 1985, Regional mapping of the phenylalanine hydroxylase gene and the phenylketonuria locus in the human genome, Proc. Natl. Acad. Sci. USA, 82, 6221, 10.1073/pnas.82.18.6221 Lidsky, 1985, Extensive restriction site polymorphism at the human phenylalanine hydroxylase locus and application in prenatal diagnosis of phenylketonuria, Am. J. Hum. Genet., 37, 619 Lidsky, 1984, The PKU locus in man is on chromosome, 12. Am. J. Hum. Genet., 36, 527 Lin, 1992, Identification of a missense phenylketonuria mutation at codon 408 in Chinese, Hum. Genet., 89, 593, 10.1007/BF00221944 Liu, 1986, Newborn screening for phenylketonuria in eleven districts, Chi. Med. J., 99, 113 Liu, 1992, Reconstitution of enzymatic activity in hepatocytes of phenylalanine hydroxylase-deficient mice, Somat. Cell. Mol. Genet., 18, 89, 10.1007/BF01233451 Lyonnet, 1989, Molecular genetics of phenylketonuria in Mediterranean countries: A mutation associated with partial phenylalanine hydroxylase deficiency, Am. J. Hum. Genet., 44, 511 Lyonnet, 1992, Time and space clusters of the French-Canadian M1V phenylketonuria mutation in France, Am. J. Hum. Genet., 51, 191 Markwell, 1985, Alternative route of infection for viruses: Entry by the asialoglycoprotein receptor of sendai virus mutant lacking its attachment protein, Proc. Natl. Acad. Sci. USA, 82, 978, 10.1073/pnas.82.4.978 Marvit, 1987, GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria, Nucleic Acids Res., 15, 5613, 10.1093/nar/15.14.5613 Matsumoto, 1988, Characteristics of Mongoloid and neighboring populations based on the genetic markers of human immunoglobulins, Hum. Genet., 80, 207, 10.1007/BF01790088 Matsuo, 1988, The development of the muscarinic acetylcholine receptor in normal and hyperphenylalaninemic rat cerebrum, Neurochem. Res., 13, 867, 10.1007/BF00970755 McBurnie, 1991, Physical growth of children treated for phenylketonuria, Ann. Hum. Biol., 18, 357, 10.1080/03014469100001662 McDonald, 1990, Pahhph-5: A mouse mutant deficient in phenylalanine hydroxylase, Proc. Natl. Acad. Sci. USA, 87, 1965, 10.1073/pnas.87.5.1965 Melle, 1991, Two distinct mutations at a single BamHI site in phenylketonuria, J. Med. Genet., 28, 38, 10.1136/jmg.28.1.38 Menozzi, 1978, Synthetic maps of human gene frequencies in Europeans, Science, 201, 786, 10.1126/science.356262 Mercer, 1984, Identification of two molecular-mass forms of phenylalanine hydroxylase that segregate independently in rats. Specific association of each form with certain rat strains, Biochem. J., 219, 891, 10.1042/bj2190891 Michael, 1993, Binding-incompetent adenovirus facilitates molecular conjugate-mediated gene transfer by the receptor-mediated endocytosis pathway, J. Biol. Chem., 268, 6866, 10.1016/S0021-9258(18)53118-5 Miller, 1989, Improved retroviral vectors for gene transfer and expression, BioTechniques, 7, 980 Mitoma, 1956, Studies on partially purified phenylalanine hydroxylase, Arch. Biochem. Biophys., 60, 476, 10.1016/0003-9861(56)90453-2 Mitoma, 1957, On the nature of enzymatic defect in phenylpyruvic oligophrenia, Proc. Soc. Exp. Biol. Med., 94, 634, 10.3181/00379727-94-23034 Morales, 1990, Sequence and expression of the Drosophila phenylalanine hydroxylase mRNA, Gene, 93, 213, 10.1016/0378-1119(90)90227-I Mullbacher, 1989, The murine cellular immune response to adenovirus type 5, Immunol Cell Biol., 67, 31, 10.1038/icb.1989.4 Murthy, 1975, Phenylalanine hydroxylase activity in liver from humans and subhuman primates: Its probable absence in kidney, Biochem. Med., 12, 392, 10.1016/0006-2944(75)90072-1 Nagatsu, 1991, Comparative studies on the structure of human tyrosine hydroxylase with those of the enzyme of various mammals, Comp. Biochem. Physiolc., 98, 203 Neda, 1991, Chemical modification of an ecotropic murine leukemia virus results in redirection of its target cell specificity, J. Biol. Chem., 266, 14143, 10.1016/S0021-9258(18)98654-0 Niederweiser, 1984, GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine and serotonin deficiencies and muscular hypotonia, Eur. J. Pediatr., 141, 208, 10.1007/BF00572762 Niederweiser, 1985, Atypical phenylketonuria with “dihydrobiopterine synthetase” deficiency: Absence of phosphate-eliminating enzyme activity demonstrated in liver, Eur. J. Pediatr., 144, 13, 10.1007/BF00491917 Niederweiser, 1986, Prenatal diagnosis of “dihydrobiopterine synthetase” deficiency, a variant form of phenylketonuria, Eur. J. Pediatr., 145, 176, 10.1007/BF00446058 Okano, 1994, Molecular and population genetics of phenylketonuria in Orientals: Correlation between phenotype and genotype, J. Inher. Metab. Dis., 17, 156, 10.1007/BF00735425 Okano, 1994, Molecular characterization of phenylketonuric mutations by analysis of phenylalanine hydroxylase mRNA from lymphoblasts in Japanese, Hum. Mol. Genet., 3, 659, 10.1093/hmg/3.4.659 Okano, 1992, Frequency and distribution of phenylketonuric mutations in Orientals, Hum. Mutat., 1, 216, 10.1002/humu.1380010307 Okano, 1991, A prevalent missense mutation in Northern Europe associated with hyperphenylalaninemia, Eur. J. Pediatr., 150, 347, 10.1007/BF01955938 Okano, 1991, Molecular basis of phenotypic heterogeneity in phenylketonuria, N. Engl. J. Med., 324, 1232, 10.1056/NEJM199105023241802 Okano, 1991, Phenylketonuria missense mutations in the Mediterranean, Genomics, 9, 96, 10.1016/0888-7543(91)90225-4 Okano, 1990, Recurrent mutation in the human phenylalanine hydroxylase gene, Am. J. Hum. Genet., 46, 919 Okano, 1990, Missense mutations associated with RFLP haplotypes 1 and 4 of the human phenylalanine hydroxylase gene, Am. J. Hum. Genet., 46, 18 Okano, 1989, Molecular genetics of PKU among Caucasians, Am. J. Hum. Genet., 45, A211 Onishi, 1991, Cloning and expression of Chromobacterium violaceum phenylalanine hydroxylase in Escherichia coli and comparison of amino acid sequence with mammalian aromatic amino acid hydroxylases, J. Biol. Chem., 266, 18454, 10.1016/S0021-9258(18)55083-3 Orkin, 1984, The mutation and polymorphism of the human β-globin gene and its surrounding DNA, Annu. Rev. Genet., 18, 131, 10.1146/annurev.ge.18.120184.001023 Ozalp, 1986, Incidence of phenylketonuria and hyperphenylalaninemia in a sample of the newborn population, J. Inher. Metab. Dis., 9, 237, 10.1007/BF01799716 PAH Gene Mutation Analysis Consortium, April 1994 (C. R. Scriver, Ed.) Paul, 1979, Linkage analysis using heterozygote detection in phenylketonuria, Clin. Genet., 16, 217, 10.1111/j.1399-0004.1979.tb00994.x Paul, 1979, Is there a heterozygote advantage in the birthweight and number of children born to PKU heterozygotes?, Am. J. Hum. Genet., 31, A104 Peng, 1988, Retroviral-mediated gene transfer and expression of human phenylalanine hydroxylase in primary mouse hepatocytes, Proc. Natl. Acad. Sci. USA, 85, 8146, 10.1073/pnas.85.21.8146 Penrose, 1935, Inheritance of phenylpyruvic amentia (phenylketonuria), Lancet, 2, 192, 10.1016/S0140-6736(01)04897-8 Penrose, 1937, Metabolic studies in phenylketonuria, Biochem. J., 31, 266, 10.1042/bj0310266 Pérez, 1993, Presence of the Mediterranean PKU mutation IVS10 in Latin America, Hum. Mol. Genet., 2, 1289, 10.1093/hmg/2.8.1289 Pérez, 1992, Mutation analysis of phenylketonuria in Spain: Prevalence of two Mediterranean mutations, Hum. Genet., 89, 341, 10.1007/BF00220555 Pigeon, 1987, Rat pheochromocytoma tyrosine hydroxylase is phosphorylated on serine 40 by an associated protein kinase, J. Biol. Chem., 262, 6155, 10.1016/S0021-9258(18)45551-2 Plank, 1992, Gene transfer into hepatocytes using asialoglycoprotein receptor mediated endocytosis of DNA complexes with an artificial tetra-antennary galactose ligand, Bioconjugate Chem., 3, 533, 10.1021/bc00018a012 Ponder, 1991, Mouse hepatocytes migrate to liver parenchyma and function indefinitely after intrasplenic transplantation, Proc. Natl. Acad. Sci. USA, 88, 1217, 10.1073/pnas.88.4.1217 Quantin, 1992, Adenovirus as an expression vector in muscle cells, In vivo. Proc. Natl. Acad. Sci. USA, 89, 2581, 10.1073/pnas.89.7.2581 Ramus, 1993, A new phenylketonuria (PKU) mutation detected by illegitimate transcription results in RNA mis-splicing: Founder effect and PKU in Australia, Am. J. Hum. Genet., 53, A1218 Ramus, 1992, CpG hotspot causes second mutation in codon 408 of the phenylalanine hydroxylase gene, Hum. Genet., 90, 147, 10.1007/BF00210760 Ramus, 1993, Comparison of genotype and intellectual phenotype in untreated PKU patients, J. Med. Genet., 30, 401, 10.1136/jmg.30.5.401 Riess, 1988, Linkage disequilibrium between RFLP haplotype 2 and the affected PAH allele in PKU families from the Berlin area of the German Democratic Republic, Hum. Genet., 78, 343, 10.1007/BF00291732 Rey, 1988, Clinical and molecular heterogeneity of phenylalanine hydroxylase deficiencies in France, Am. J. Hum. Genet., 43, 914 Robson, 1984, Sequence comparison of rat liver phenylalanine hydroxylase and its cDNA clones, Biochemistry, 23, 5671, 10.1021/bi00319a001 Robson, 1982, Polysome immunoprecipitation of phenylalanine hydroxylase mRNA from rat liver and cloning of its cDNA, Proc. Natl. Acad. Sci. USA, 79, 4701, 10.1073/pnas.79.15.4701 Rosenblatt, 1968, Heterogeneity in genetic control of phenylalanine metabolism in man, Nature, 218, 677, 10.1038/218677a0 Rosenfeld, 1991, Adenovirus-mediated transfer of a recombinant alpha-1-antitrypsin gene to the lung epithelium, In vivo. Science, 252, 431 Rosenfeld, 1992, In vivo transfer of the human CFTR gene to the airway epithelium, Cell, 68, 143, 10.1016/0092-8674(92)90213-V Sarkar, 1989, Access to a messenger RNA sequence or its protein product is not limited by tissue or species specificity, Science, 244, 331, 10.1126/science.2565599 Saugstad, 1973, Increased “reproductive casualty” in heterozygotes for phenylketonuria, Clin. Genet., 4, 105, 10.1111/j.1399-0004.1973.tb01130.x Saugstad, 1977, Heterozygote advantage for the phenylketonuria allele, J. Med. Genet., 14, 20, 10.1136/jmg.14.1.20 Scriver, 1988, Mendelian hyperphenylalaninemia, Annu. Rev. Genet., 22, 301, 10.1146/annurev.ge.22.120188.001505 Scriver, 1989, The hyperphenylalaninemias, 495 Scriver, 1993, Associations between populations, PKU mutations and RFLP haplotypes at the PAH locus: An overview, Dev. Brain Dys., 6, 11 Shedlovsky, 1993, Mouse models of human phenylketonuria, Genetics, 134, 1205, 10.1093/genetics/134.4.1205 Shiman, 1980, Substrate activation of phenylalanine hydroxylase. A kinetic characterization, J. Biol. Chem., 255, 4793, 10.1016/S0021-9258(19)85567-9 Shirahase, 1991, A new single base substitution in a Japanese phenylketonuria (PKU) patient, Brain Dev., 13, 283, 10.1016/S0387-7604(12)80064-7 Shirahase, 1992, Genetic study on Japanese classical phenylketonuria (family analysis by PCR-SSCP analysis), Acta Pediatr. Jpn., 96, 939 Smith, 1988, Behaviour disturbance in 8-year-old children with early-treated phenylketonuria, J. Pediatr., 112, 403, 10.1016/S0022-3476(88)80320-2 Smith, 1978, Effect of stopping low-phenylalanine diet on intellectual progress of children with phenylketonuria, Br. Med. J., 2, 723, 10.1136/bmj.2.6139.723 Smith, 1984, Two apparent molecular weight forms of human and monkey phenylalanine hydroxylase are due to phosphorylation, J. Biol. Chem., 259, 11284, 10.1016/S0021-9258(18)90860-4 Sokal, 1991, Genetic evidence for the spread of agriculture in Europe by demic diffusion, Nature, 351, 143, 10.1038/351143a0 Speer, 1986, Typing of families with classical phenylketonuria using three alleles of the Hind III linked restriction fragment polymorphism, detectable with a phenylalanine hydroxylase cDNA probe, Clin. Genet., 29, 491, 10.1111/j.1399-0004.1986.tb00549.x Stoll, 1991, Isolation and structural characterization of the murine tryptophan hydroxylase gene, J. Neurosci. Res., 28, 457, 10.1002/jnr.490280402 Stratford-Perricaudet, 1990, Evaluation of the transfer and expression in mice of an enzyme-encoding gene using a human adenovirus vector, Hum. Gene Ther., 1, 241, 10.1089/hum.1990.1.3-241 Stuhrmann, 1989, Haplotype analysis of the phenylalanine hydroxylase gene in Turkish phenylketonuria families, Clin. Genet., 36, 117, 10.1111/j.1399-0004.1989.tb03173.x Sullivan, 1985, Phenylalanine hydroxylase deletion mutant from a patient with classical PKU, Am. J. Hum. Genet., 37, A177 Sullivan, 1989, Haplotype distribution of the human phenylalanine hydroxylase locus in Scotland and Switzerland, Am. J. Hum. Genet., 44, 652 Svensson, 1990, Two mutations within the coding sequence of the phenylalanine hydroxylase gene, Hum. Genet., 85, 300, 10.1007/BF00206750 Svensson, 1991, Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus and their relation to phenotype in Swedish phenylketonuria families, Hum. Genet., 87, 11, 10.1007/BF01213084 Svensson, 1992, Two missense mutations causing hyperphenylalaninemia associated with DNA haplotype 12, Hum. Mutat., 1, 129, 10.1002/humu.1380010208 Svensson, 1993, Relation between genotype and phenotype in Swedish phenylketonuria and hyperphenylalaninemia patients, Eur. J. Ped., 152, 132, 10.1007/BF02072490 Svensson, 1993, Three polymorphisms but no disease-causing mutations in the proximal part of the promoter of the phenylalanine hydroxylase gene, Eur. J. Hum. Gen., 1, 306, 10.1159/000472429 Takahashi, 1992, Novel phenylketonuria mutation detected by analysis of ectopically transcribed phenylalanine hydroxylase mRNA from lymphoblast, Lancet, 340, 1473, 10.1016/0140-6736(92)92665-3 Takahashi, 1994, Ectopic transcription: An application to the analysis of splicing errors in phenylalanine hydroxylase mRNA, Acta Paediatr., 10.1111/j.1651-2227.1994.tb13449.x Takarada, 1993, Phenylketonuria mutant alleles in different populations: Missense mutation in exon 7 of the phenylalanine hydroxylase gene, Clin. Chem., 39, 2354, 10.1093/clinchem/39.11.2354 Takarada, 1993, Novel homozygous mutation of phenylalanine hydroxylase gene in a Chinese patient with phenylketonuria, Clin. Chem., 39, 1350, 10.1093/clinchem/39.6.1350 Takarada, 1993, Novel mutation in exon 7 of the phenylalanine hydroxylase gene in a Chinese patient with phenylketonuria, Clin. Chem., 39, 2357, 10.1093/clinchem/39.11.2357 Thompson, 1991, Magnetic resonance imaging changes in early treated patients with phenylketonuria, Lancet, 337, 1224, 10.1016/0140-6736(91)92894-8 Treacy, 1993, “Celtic” phenylketonuria chromosomes found? Evidence in two regions of Quebec province, Eur. J. Hum. Genet., 22, 220 Trefz, 1981, In vitro residual activities of the phenylalanine hydroxylating system in phenylketonuria and variants, J. Inher. Metab. Dis., 4, 101, 10.1007/BF02263611 Trefz, 1993, Genotype-phenotype correlations in phenylketonuria, Clin. Chim. Acta, 217, 15, 10.1016/0009-8981(93)90233-T Trefz, 1979, Sensitive in vivo assay of the phenylalanine hydroxylating system with a small intravenous dose of heptadeutero L-phenylalanine using high pressure liquid chromatography and capillary gas chromatography/mass fragmentography, Clin. Chim. Acta, 99, 211, 10.1016/0009-8981(79)90264-X Trefz, 1988, PKU and non-PKU hyperphenylalaninemia: Differentiation, indication for therapy and therapeutic results, Acta Paediatr. Jpn., 30, 397, 10.1111/j.1442-200X.1988.tb02528.x Trefz, 1990, RFLP-patterns in Japanese PKU families: New polymorphisms for the mutant phenylalanine hydroxylase gene, Hum. Genet., 85, 121, 10.1007/BF00276336 Tsai, 1990, Phenylketonuria mutation in Chinese haplotype 44 identical with haplotype 2 mutation in northern-European Caucasians, Hum. Genet., 84, 409, 10.1007/BF00195810 Turek, 1993, Endocytosis of folate-protein conjugates: Ultrastructural localization in KB cells, J. Cell Sci., 106, 4223, 10.1242/jcs.106.1.423 Tyfield, 1991, Molecular heterogeneity at the phenylalanine hydroxylase locus in the population of the south-west of England, J. Med. Genet., 28, 244, 10.1136/jmg.28.4.244 Tyfield, 1993, Molecular basis of phenylketonuria in an English population, Dev. Brain Dys., 6, 60 Udenfriend, 1952, The enzymatic conversion of phenylalanine to tyrosine, J. Biol. Chem., 194, 503, 10.1016/S0021-9258(18)55802-6 Verelst, 1993, Heterogeneity of phenylketonuria in Belgium, Dev. Brain Dys., 6, 97 Verelst, 1988, Restriction fragment length polymorphism in the phenylalanine hydroxylase locus in the Belgian population, Abstr. SSIEM, London. Wagner, 1991, DNA-binding transferrin conjugates as functional gene-delivery agents: Synthesis by linkage of polylysine or ethidium homodimer to the transferrin carbohydrate moiety, Bioconjugate Chem., 2, 226, 10.1021/bc00010a006 Wagner, 1992, Coupling of adenovirus to transferrin-polylysine/DNA complexes greatly enhances receptor-mediated gene delivery and expression of transfected genes, Proc. Natl. Acad. Sci. USA, 89, 6099, 10.1073/pnas.89.13.6099 Wagner, 1990, Transferrin-polycation conjugates as carriers for DNA uptake into cells, Proc. Natl. Acad. Sci. USA, 87, 3410, 10.1073/pnas.87.9.3410 Wang, 1989, Molecular genetics of PKU in Orientals: Linkage disequilibrium between a termination mutation and haplotype 4 of the phenylalanine hydroxylase gene, Am. J. Hum. Genet., 45, 675 Wang, 1990, Molecular genetics of PKU in Eastern Europe: A nonsense mutation associated with haplotype 4 of the phenylalanine hydroxylase gene, Somat. Cell. Mol. Genet., 16, 85, 10.1007/BF01650483 Wang, 1991, Founder effect of a prevalent PKU mutation in the Oriental population, Proc. Natl. Acad. Sci. USA, 88, 2146, 10.1073/pnas.88.6.2146 Wang, 1991, Missense mutations prevalent in Orientals with phenylketonuria: Molecular characterization and clinical implications, Genomics, 10, 449, 10.1016/0888-7543(91)90331-8 Wang, 1991, Identification of a novel PKU mutation in Chinese: Further evidence for multiple origins of PKU in Asia, Am. J. Hum. Genet., 48, 628 Wang, 1992, Identification of three novel PKU mutations among Chinese: Evidence for recombination or recurrent mutation at the PAH locus, Genomics, 10, 449, 10.1016/0888-7543(91)90331-8 Wedemeyer, 1991, PCR detection of the MspI (Aa) RFLP at the human phenylalanine hydroxylase (PAH) locus, Nucleic Acids Res., 19, 1959, 10.1093/nar/19.8.1959 Weinstein, 1993, A missense mutation, S349P, completely inactivates phenylalanine hydroxylase and is involved in different hyperphenylalaninemias in North African Jews, Hum. Genet., 90, 645, 10.1007/BF00202483 Wilson, 1992, Hepatocyte-directed gene transfer in vivo leads to transient improvement in hypercholesterolemia in low density lipoprotein receptor-deficient rabbits, J. Biol. Chem., 267, 963, 10.1016/S0021-9258(18)48379-2 Woo, 1983, Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria, Nature, 306, 151, 10.1038/306151a0 Woolf, 1979, Late onset phenylalanine intoxication, J. Inher. Metab. Dis., 2, 19, 10.1007/BF01805558 Woolf, 1986, The heterozygote advantage of phenylketonuria, Am. J. Hum. Genet., 38, 773 Woolf, 1951, Phenylketonuria with a study of the effect upon it of glutamic acid, Arch. Dis. Child., 26, 487, 10.1136/adc.26.130.487 Woolf, 1955, Treatment of phenylketonuria with a diet low in phenylalanine, Br. Med. J., 1, 57, 10.1136/bmj.1.4905.57 Woolf, 1975, Phenylketonuria as a balanced polymorphism: The nature of the heterozygote advantage, Ann. Hum. Genet., 38, 461, 10.1111/j.1469-1809.1975.tb00635.x Wu, 1987, Receptor-mediated in vitro gene transformation by a soluble DNA carrier system, J. Biol. Chem., 262, 4429, 10.1016/S0021-9258(18)61209-8 Wu, 1988, Receptor-mediated gene delivery and expression in, Vivo. J. Biol. Chem., 263, 14621, 10.1016/S0021-9258(18)68081-0 Wu, 1991, Receptor-mediated gene delivery, In vivo. J. Biol. Chem., 266, 14338, 10.1016/S0021-9258(18)98689-8 Wu, 1989, Targeting genes: Delivery and persistent expression of a foreign gene driven by mammalian regulatory elements, In vivo. J. Biol. Chem., 264, 16985, 10.1016/S0021-9258(18)71447-6 Yamashita, 1985, Purification of phenylalanine hydroxylase from human adult and foetal livers with a monoclonal antibody, Biochem. Biophys. Res. Commun., 133, 202, 10.1016/0006-291X(85)91861-3 Yang, 1994, Cellular immunity to viral antigens limits E1-deleted adenovirus for gene therapy, Proc. Natl. Acad. Sci. USA, 91, 4407, 10.1073/pnas.91.10.4407 Yang, 1993, An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer, Proc. Natl. Acad. Sci. USA, 90, 4601, 10.1073/pnas.90.10.4601 Zenke, 1990, Receptor-mediated endocytosis of transferrin-polycation conjugates: An efficient way to introduce DNA into hematopoietic cells, Proc. Natl. Acad. Sci. USA, 87, 3655, 10.1073/pnas.87.10.3655 Zhao, 1989, Gm and Km allotypes in 74 Chinese populations: A hypothesis for the origin of the Chinese nation, Hum. Genet., 83, 101, 10.1007/BF00286699 Zygulska, 1991, Molecular analysis of PKU haplotypes in the population of southern Poland, Hum. Genet., 86, 292, 10.1007/BF00202412