Genetics of Phenylketonuria: Then and Now

Human Mutation

Volumn 37, Issue 6, 2016, Pages 508-515

  Blau, Nenad ^a  

^a UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

Author keywords

Hyperphenylalaninaemia; PAH; Phenylalanine hydroxylase; Phenylketonuria; PKU; Sapropterin; Tetrahydrobiopterin

Indexed keywords

6 PYRUVOYLTETRAHYDROPTERIN SYNTHASE; TETRAHYDROBIOPTERIN; BIOPTERIN; PHENYLALANINE 4 MONOOXYGENASE; SAPROPTERIN;

DISEASE SEVERITY; GENE MUTATION; GENETIC ANALYSIS; GENETIC VARIATION; GENOTYPE; GENOTYPE PHENOTYPE CORRELATION; HUMAN; HYPERPHENYLALANINEMIA; MOLECULAR GENETICS; PHENYLKETONURIA; PRIORITY JOURNAL; REVIEW; ANALOGS AND DERIVATIVES; GENETICS; HISTORY; METABOLISM; MUTATION; PHENOTYPE;

BIOPTERIN; HISTORY, 20TH CENTURY; HISTORY, 21ST CENTURY; HUMANS; MUTATION; PHENOTYPE; PHENYLALANINE HYDROXYLASE; PHENYLKETONURIAS;

EID: 84960916057     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22980     Document Type: Review

References (98)

1. Arturo EC, Gupta K, Heroux A, Stith L, Cross PJ, Parker EJ, Loll PJ, Jaffe EK. 2016. First structure of full-length mammalian phenylalanine hydroxylase reveals the architecture of an autoinhibited tetramer. Proc Natl Acad Sci U S A 113(9):2394-2399.
2. Bartholomé K. 1974. A new molecular defect in phenylketonuria. Lancet 2:1580.
3. Belanger-Quintana A, Dokoupil K, Gokmen-Ozel H, Lammardo AM, Macdonald A, Motzfeldt K, Nowacka M, Robert M, van Rijn M, Ahring K. 2012. Diet in phenylketonuria: a snapshot of special dietary costs and reimbursement systems in 10 international centers. Mol Genet Metab 105:390-394.
4. Benit P, Rey F, Blandin-Savoja F, Munnich A, Abadie V, Rey J. 1999. The mutant genotype is the main determinant of the metabolic phenotype in phenylalanine hydroxylase deficiency. Mol Genet Metab 68:43-47.
5. Bercovich D, Elimelech A, Zlotogora J, Korem S, Yardeni T, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y. 2008. Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene. J Hum Genet 53:407-418.
6. Bickel H, Gerrard JW, Hickmans EM. 1953. Influence of phenylalanine intake on phenylketonuria. Lancet 2:812-819.
7. Blau N. 2010. Sapropterin dihydrochloride for phenylketonuria and tetrahydrobiopterin deficiency. Expert Rev Endocrinol Metab 5:483-494.
8. Blau N, Heizmann CW, Sperl W, Korenke GC, Hoffmann GF, Smooker PM, Cotton RGH. 1992. Atypical (mild) forms of dihydropteridine reductase deficiency-neurochemical evaluation and mutation detection. Pediatr Res 32:726-730.
9. Blau N, Longo N. 2015. Alternative therapies to address the unmet medical needs of patients with phenylketonuria. Expert Opin Pharmacother 16:1-10.
10. Blau N, Shen N, Carducci C. 2014. Molecular genetics and diagnosis of phenylketonuria: state of the art. Expert Rev Mol Diagn 14:655-671.
11. Blau N, Thöny B, Cotton RGH, Hyland K. 2001. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill. pp 1725-1776.
12. Blau N, Van Spronsen FJ, Levy HL. 2010. Phenylketonuria. Lancet 376:1417-1427.
13. Buck PS. 1992. The child who never grew. Bethesda, MD: Woodbine House.
14. Bueno MA, Gonzalez-Lamuno D, Delgado-Pecellin C, Aldamiz-Echevarria L, Perez B, Desviat LR, Couce ML. 2013. Molecular epidemiology and genotype-phenotype correlation in phenylketonuria patients from South Spain. J Hum Genet 58:279-284.
15. Burlina A, Blau N. 2014. Tetrahydrobiopterin disorders presenting with hyperphenylalaninemia. In: Hoffmann FG, Blau N, editors. Congenital nueurotransmitter disorders: a clinical approach. Huppauge, NY: Nova Publishers Inc.
16. Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, Brown CS, Burlina AB, Burton BK, Chang CS, et al. 2014. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab 112:87-122.
17. Carluccio C, Fraternali F, Salvatore F, Fornili A, Zagari A. 2015. Towards the identification of the allosteric Phe-binding site in phenylalanine hydroxylase. J Biomol Struct Dyn 34:497-507.
18. Cotton RGH. 1986. A model for hyperphenylalaninaemia due to tetrahydrobiopterin deficiency. J Inherit Metab Dis 9:4-14.
19. Cotton RGH, Jennings I, Bracco G, Ponzone A, Guardamagna O. 1986a. Tetrahydrobiopterin non-responsiveness in dihydropteridine reductase deficiency is associated with the presence of mutant protein. J Inherit Metab Dis 9:239-243.
20. Cotton RGH, Jennings IG, Bracco G, Ponzone A, Guardamagna O. 1986b. Correlation of dihydropteridine reductase cross reacting material with non responsiveness to a tetrahydrobiopterin load. In: Cooper BA, Whitehead VM, editors. Chemistry and biology of pteridines, 1986. Berlin, Germany: Walter de Gruyter. pp 407-414.
21. Dahl HH, Hutchison W, McAdam W, Wake S, Morgan FJ, Cotton RG. 1987. Human dihydropteridine reductase: characterisation of a cDNA clone and its use in analysis of patients with dihydropteridine reductase deficiency. Nucleic Acids Res 15:1921-1932.
22. Dahl HH, Wake S, Cotton RG, Danks DM. 1988. The use of restriction fragment length polymorphisms in prenatal diagnosis of dihydropteridine reductase deficiency. J Med Genet 25:25-28.
23. Danecka MK, Woidy M, Zschocke J, Feillet F, Muntau AC, Gersting SW. 2015. Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria. J Med Genet 52:175-185.
24. Daniele A, Scala I, Cardillo G, Pennino C, Ungaro C, Sibilio M, Parenti G, Esposito L, Zagari A, Andria G, Salvatore F. 2009. Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy. FEBS J 276:2048-2059.
25. Danks DM, Cotton RG, Schlesinger P. 1975. Tetrahydrobiopterin treatment of variant form of phenylketonuria. Lancet 2:1043.
26. Danks DM, Cotton RG, Schlesinger P. 1979. Diagnosis of malignant hyperphenylalaninaemia. Arch Dis Child 54:329-330.
27. Dianzani I, de Santis L, Smooker PM, Gough TJ, Alliaudi C, Brusco A, Spada M, Blau N, Dobos M, Zhang HP, Yang N, Ponzone A, et al. 1998. Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations. Hum Mutat 12:267-273.
28. DiLella AG, Marvit J, Brayton K, Woo SL. 1987. An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2. Nature 327:333-336.
29. Eisensmith RC, Woo SL. 1992. Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. Hum Mutat 1:13-23.
30. Erlandsen H, Pey AL, Gamez A, Perez B, Desviat LR, Aguado C, Koch R, Surendran S, Tyring S, Matalon R, Scriver CR, Ugarte M, et al. 2004. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Natl Acad Sci U S A 101:16903-16908.
31. Erlandsen H, Stevens RC. 1999. The structural basis of phenylketonuria. Mol Genet Metab 68:103-125.
32. Fiege B, Blau N. 2007. Assessment of tetrahydrobiopterin (BH4)-responsiveness in phenylketonuria. J Pediatr 150:627-630.
33. Finger S, Christ SE. 2004. Pearl S. Buck and phenylketonuria (PKU). J Hist Neurosci 13:44-57.
34. Firgaira FA, Choo KH, Cotton RG, Danks DM. 1981a. Heterogeneity of the molecular defect in human dihydropteridine reductase deficiency. Biochem J 198:677-682.
35. Firgaira FA, Choo KH, Cotton RGH, Danks DM. 1981b. Molecular and immunological comparison of human dihydropteridine reductase in liver, cultured fibroblasts, and continuous lymphoid cells. Biochem J 197:45-53.
36. Firgaira FA, Cotton RG, Danks DM. 1979. Dihydropteridine reductase deficiency diagnosis by assays on peripheral blood-cells. Lancet 2:1260-1263.
37. Fölling IA. 1934. Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Inbicillität. Hoppe Seylers Z Physiol Chem 227:169.
38. Forrest SM, Dahl HH, Howells DW, Dianzani I, Cotton RG. 1991. Mutation detection in phenylketonuria by using chemical cleavage of mismatch: importance of using probes from both normal and patient samples. Am J Hum Genet 49:175-183.
39. Gamez A, Perez B, Ugarte M, Desviat LR. 2000. Expression analysis of phenylketonuria mutations. Effect on folding and stability of the phenylalanine hydroxylase protein. J Biol Chem 275:29737-29742.
40. Gersting SW, Kemter KF, Staudigl M, Messing DD, Danecka MK, Lagler FB, Sommerhoff CP, Roscher AA, Muntau AC. 2008. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am J Hum Genet 83:5-17.
41. Gjetting T, Petersen M, Guldberg P, Guttler F. 2001. In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation. Mol Genet Metab 72:132-143.
42. Guthrie R, Susi A. 1963. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32:338-343.
43. Heintz C, Cotton RG, Blau N. 2013. Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase and importance of genotypes for pharmacological therapy of phenylketonuria. Hum Mutat 34:927-936.
44. Howells DW, Forrest SM, Dahl HH, Cotton RG. 1990. Insertion of an extra codon for threonine is a cause of dihydropteridine reductase deficiency. Am J Hum Genet 47:279-285.
45. Jaffe EK, Stith L, Lawrence SH, Andrake M, Dunbrack RL, Jr. 2013. A new model for allosteric regulation of phenylalanine hydroxylase: implications for disease and therapeutics. Arch Biochem Biophys 530:73-82.
46. Jennings IG, Cotton RG, Kobe B. 2000. Structural interpretation of mutations in phenylalanine hydroxylase protein aids in identifying genotype-phenotype correlations in phenylketonuria. Eur J Hum Genet 8:683-696.
47. John SW, Scriver CR, Laframboise R, Rozen R. 1992. In vitro and in vivo correlations for I65T and M1V mutations at the phenylalanine hydroxylase locus. Hum Mutat 1:147-153.
48. Kasnauskiene J, Cimbalistiene L, Kucinskas V. 2003. Validation of PAH genotype-based predictions of metabolic phenylalanine hydroxylase deficiency phenotype: investigation of PKU/MHP patients from Lithuania. Med Sci Monit 9:CR142-CR146.
49. Kaufman S. 1987. Enzymology of the phenylalanine-hydroxylating system. Enzyme 38(1-4):286-295.
50. Kayaalp E, Treacy E, Waters PJ, Byck S, Nowacki P, Scriver CR. 1997. Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. Am J Hum Genet 61:1309-1317.
51. Konecki DS, Wang Y, Trefz FK, Lichter-Konecki U, Woo SL. 1992. Structural characterization of the 5′ regions of the human phenylalanine hydroxylase gene. Biochemistry 31:8363-8368.
52. Kure S, Hou DC, Ohura T, Iwamoto H, Suzuki S, Sugiyama N, Sakamoto O, Fujii K, Matsubara Y, Narisawa K. 1999. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135:375-378.
53. Leandro J, Nascimento C, de Almeida IT, Leandro P. 2006. Co-expression of different subunits of human phenylalanine hydroxylase: evidence of negative interallelic complementation. Biochim Biophys Acta 1762:544-550.
54. Longo N. 2009. Disorders of biopterin metabolism. J Inherit Metab Dis 32:333-342.
55. MacDonald A, Blau N. 2013. Treatment. In: Blau N, Burton BK, Levy HL, MacDonald A, Thöny B, van Spronsen F, editors. Phenylketonuria and BH4 deficiencies. Bremen, London, Boston: UNI-MED.
56. MacDonald A, Gokmen-Ozel H, van Rijn M, Burgard P. 2010. The reality of dietary compliance in the management of phenylketonuria. J Inherit Metab Dis 33:665-670.
57. MacDonald A, Rocha JC, van Rijn M, Feillet F. 2011. Nutrition in phenylketonuria. Mol Genet Metab 104Suppl:S10-S18.
58. Mitchell JJ, Trakadis YJ, Scriver CR. 2011. Phenylalanine hydroxylase deficiency. Genet Med 13:697-707.
59. Muntau AC, Leandro J, Staudigl M, Mayer F, Gersting SW. 2014. Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators. J Inherit Metab Dis 37:505-523.
60. Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA. 2002. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347:2122-2132.
61. Opladen T, Hoffmann FG, Blau N. 2012. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 35:963-973.
62. Penrose LS. 1935. Inheritance of phenylpyruvic amentia (phenylketonuria). Lancet 2:192-194.
63. Pey AL, Desviat LR, Gamez A, Ugarte M, Perez B. 2003. Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat 21:370-378.
64. Pey AL, Perez B, Desviat LR, Martinez MA, Aguado C, Erlandsen H, Gamez A, Stevens RC, Thorolfsson M, Ugarte M, Martinez A. 2004. Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations. Hum Mutat 24:388-399.
65. Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L. 2013. Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness. Gene 526:347-355.
66. Ponzone A, Guardamagna O, Ferraris S, Bracco G, Niederwieser A, Cotton RG. 1988. Two mutations of dihydropteridine reductase deficiency. Arch Dis Child 63:154-157.
67. Ponzone A, Guardamagna O, Ferraris S, Ferrero GB, Dianzani I, Cotton RGH. 1991. Tetrahydrobiopterin loading test in hyperphenylalaninemia. Pediatr Res 30:435-438.
68. Porta F, Mussa A, Concolino D, Spada M, Ponzone A. 2009. Dopamine agonists in 6-pyruvoyl tetrahydropterin synthase deficiency. Neurology 73:633-637.
69. Ratnam S, Ratnam M, Cotton RG, Jennings IG, Freisheim JH. 1989. Anti-idiotypic antibodies elicited by pterin recognize active site epitopes in dihydrofolate reductases and dihydropteridine reductase. Arch Biochem Biophys 275:344-353.
70. Reblova K, Hruba Z, Prochazkova D, Pazdirkova R, Pouchla S, Fajkusova L. 2013. Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations. Clin Chim Acta 419:1-10.
71. Rossi L, Pierige F, Carducci C, Gabucci C, Pascucci T, Canonico B, Bell SM, Fitzpatrick PA, Leuzzi V, Magnani M. 2014. Erythrocyte-mediated delivery of phenylalanine ammonia lyase for the treatment of phenylketonuria in BTBR-Pah mice. J Control Release 194:37-44.
72. Santos-Sierra S, Kirchmair J, Perna AM, Reiss D, Kemter K, Roschinger W, Glossmann H, Gersting SW, Muntau AC, Wolber G, Lagler FB. 2012. Novel pharmacological chaperones that correct phenylketonuria in mice. Hum Mol Genet 21:1877-1887.
73. Scriver CR. 2007. The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat 28:831-845.
74. Scriver CR, Hurtubise M, Konecki D, Phommarinh M, Prevost L, Erlandsen H, Stevens R, Waters PJ, Ryan S, McDonald D, Sarkissian C. 2003. PAHdb 2003: what a locus-specific knowledgebase can do. Hum Mutat 21:333-344.
75. Scriver CR, Waters PJ, Sarkissian C, Ryan S, Prevost L, Cote D, Novak J, Teebi S, Nowacki PM. 2000. PAHdb: a locus-specific knowledgebase. Hum Mutat 15:99-104.
76. Shen N, Heintz C, Thiel C, Okun JG, Hoffmann FG, Blau N. 2016. Co-expression of phenylalanine hydroxylase variants and effects of interallelic complementation on in vitro enzyme activity and genotypephenotype correlation. Mol Genet Metab.[Epub ahead of print], doi: 10.1016/j.ymgme.2016.01.004
77. Shintaku H, Ohwada M, Aoki K, Kitagawa T, Yamano T. 2008. Diagnosis of tetrahydrobiopterin (BH4) responsive mild phenylketonuria in Japan over the past 10 years. Ann Acad Med Singapore 37(12 Suppl):77-82.
78. Smith I, Clayton BE, Wolff OH. 1975. New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction. Lancet 1:1108-1111.
79. Smooker PM, Gough TJ, Cotton RG, Alliaudi C, de Sanctis L, Dianzani I. 1999. A series of mutations in the dihydropteridine reductase gene resulting in either abnormal RNA splicing or DHPR protein defects. Mutations in brief no. 244. Online. Hum Mutat 13:503-504.
80. Staudigl M, Gersting SW, Danecka MK, Messing DD, Woidy M, Pinkas D, Kemter KF, Blau N, Muntau AC. 2011. The interplay between genotype, metabolic state, and cofactor treatment governs phenylalanine hydroxylase function and drug response. Hum Mol Genet 20:2628-2641.
81. Strisciuglio P, Concolino D. 2014. New strategies for the treatment of phenylketonuria (PKU). Metabolites 4:1007-1017.
82. Tao J, Li N, Jia H, Liu Z, Li X, Song J, Deng Y, Jin X, Zhu J. 2015. Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria. Pediatr Res 78:691-699.
83. Thöny B, Blau N. 2006. Mutations in the BH4-metabolizing genes GTP cyclohydroalse I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase genes. Hum Mutat 27:870-878.
84. Trefz FK, Burgard P, Konig T, Goebel-Schreiner B, Lichter-Konecki U, Konecki D, Schmidt E, Schmidt H, Bickel H. 1993. Genotype-phenotype correlations in phenylketonuria. Clin Chim Acta 217:15-21.
85. Trefz FK, Burton BK, Longo N, Casanova MM, Gruskin DJ, Dorenbaum A, Kakkis ED, Crombez EA, Grange DK, Harmatz P, Lipson MH, Milanowski A, et al. 2009. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr 154:700-707.
86. Trujillano D, Perez B, Gonzalez J, Tornador C, Navarrete R, Escaramis G, Ossowski S, Armengol L, Cornejo V, Desviat LR, Ugarte M, Estivill X. 2014. Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing. Eur J Hum Genet 22:528-534.
87. Trunzo R, Santacroce R, D'Andrea G, Longo V, De Girolamo G, Dimatteo C, Leccese A, Bafunno V, Lillo V, Papadia F, Margaglione M. 2015. Phenylalanine hydroxylase deficiency in South Italy: genotype-phenotype correlations, identification of a novel mutant PAH allele and prediction of BH responsiveness. Clin Chim Acta 450:51-55.
88. Underhaug J, Aubi O, Martinez A. 2013. Phenylalanine hydroxylase misfolding and pharmacological chaperones. Curr Top Med Chem 12:2534-2545.
89. Viecelli HM, Harbottle RP, Wong SP, Schlegel A, Chuah MK, Vandendriessche T, Harding CO, Thony B. 2014. Treatment of phenylketonuria using minicircle-based naked-DNA gene transfer to murine liver. Hepatology 60:1035-1043.
90. Waters PJ, Parniak MA, Nowacki P, Scriver CR. 1998. In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function. Hum Mutat 11:4-17.
91. Werner ER, Blau N, Thöny B. 2011. Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 438:397-414.
92. Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N. 2015. Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria. Eur J Hum Genet 23:302-309.
93. Woo SL, Lidsky AS, Güttler F, Chandra T, Robson KJ. 1983. Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature 306:151-155.
94. Ye J, Yang Y, Yu W, Zou H, Jiang J, Yang R, Shang S, Gu X. 2013. Demographics, diagnosis and treatment of 256 patients with tetrahydrobiopterin deficiency in mainland China: results of a retrospective, multicentre study. J Inherit Metab Dis 36:893-901.
95. Yew NS, Dufour E, Przybylska M, Putelat J, Crawley C, Foster M, Gentry S, Reczek D, Kloss A, Meyzaud A, Horand F, Cheng SH, Godfrin Y. 2013. Erythrocytes encapsulated with phenylalanine hydroxylase exhibit improved pharmacokinetics and lowered plasma phenylalanine levels in normal mice. Mol Genet Metab 109:339-344.
96. Zhang S, Fitzpatrick PF. 2016. Identification of the allosteric site for phenylalanine in rat phenylalanine hydroxylase. J Biol Chem.[Epub ahead of print], doi: 10.1074/jbc.M115.709998
97. Zhang S, Hinck AP, Fitzpatrick PF. 2015. The amino acid specificity for activation of phenylalanine hydroxylase matches the specificity for stabilization of regulatory domain dimers. Biochemistry 54:5167-5174.
98. Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens R, Thöny B, Blau N. 2008. Molecular genetics of tetrahydrobiopterin responsive phenylalanine hydroxylase deficiency. Hum Mutat 29:167-175.