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The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

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JIMD Reports, Volume 14

Part of the book series: JIMD Reports ((JIMD,volume 14))

Abstract

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutation screening was carried out in a large cohort of PKU patients from New South Wales, Australia. Pathogenic mutations were identified in 99% of the alleles screened, with the two most common mutations (p.R408W and IVS12+1G>A) accounting for 30.7% of alleles. Most individuals were compound heterozygotes for previously reported mutations, but four novel mutations (c.163+1G>T, c.164-2A>G, c.461A>T [p.Y154F], and c.510-1G>A) and a novel polymorphism (c.60+62C>T) were also identified. A number of patients have been previously tested for their response to dietary supplementation of tetrahydrobiopterin (BH4), the cofactor of PAH. Correlation between genotype and the responses revealed that although genotype is a major determinant of BH4 responsiveness, patients with the same genotype may also show disparate responses to this treatment. A clinical and biochemical evaluation should be undertaken to determine the effectiveness of PKU treatment by supplementation of BH4.

Competing interests: None declared

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References

  • Acosta A, Silva W Jr, Carvalho T, Gomes M, Zago M (2001) Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian patients with phenylketonuria. Hum Mutat 17(2):122–130

    Article  PubMed  CAS  Google Scholar 

  • Anjema K, Venema G, Hostede FC et al (2011) The 48-h tetrahydrobiopterin loading test in patients with phenylketonuria: evaluation of protocol and influence of baseline phenylalanine concentration. Mol Genet Metab 104:S60–S63

    Article  PubMed  CAS  Google Scholar 

  • Aulehla-Scholz C, Heilbronner H (2003) Mutation spectrum in German patients with phenylalanine hydroxylase deficiency. Hum Mutat 21:399–400

    Article  PubMed  Google Scholar 

  • Australian Bureau of Statistics (2012) Migration. Australian Bureau of Statistics, Canberra

    Google Scholar 

  • Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney HL (1999) Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest 104:375–381

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bénit P, Rey F, Blandin-Savoja F, Munnich A, Abadie V, Rey J (1999) The mutant genotype is the main determinant of the metabolic in phenylalanine hydroxylase deficiency. Mol Genet Metab 68:43–47

    Article  PubMed  Google Scholar 

  • Bercovich D, Elimelech A, Zlotogora J et al (2008) Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene. J Hum Genet 53:417–418

    Article  Google Scholar 

  • Bernegger C, Blau N (2002) High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1919 patients observed from 1988 to 2002. Mol Genet Metab 77:304–313

    Article  PubMed  CAS  Google Scholar 

  • Birk Møller L, Nygren AOH, Scott P et al (2007) Low proportion of whole exon deletions causing phenylketonuria in Denmark and Germany. Hum Mutat 28:207

    Article  PubMed  Google Scholar 

  • Blau N, Van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376:1417–1427

    Article  PubMed  CAS  Google Scholar 

  • Boneh A, Francis DEM, Humphrey M, Upton HJ, Peters HL (2005) Three-year audit of the hyperphenylalaninaemia/phenylketonuria spectrum in Victoria. J Paediatr Child Health 42:496–498

    Article  Google Scholar 

  • Bräutigam S, Kujat A, Kirst P, Seidel J, Lüleyap HU, Froster UG (2003) DHPLC mutation analysis of phenylketonuria. Mol Genet Metab 78:205–210

    Article  PubMed  Google Scholar 

  • Cajigal S (2008) FDA approves drug for phenylketonuria. Neurol Today 8:6

    Article  Google Scholar 

  • Chien Y-H, Chiang S-C, Huang A et al (2004) Mutation spectrum in Taiwanese patients with phenylalanine hydroxylase deficiency and a founder effect for the R241C mutation. Hum Mutat 23:206

    Article  PubMed  Google Scholar 

  • den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12

    Article  Google Scholar 

  • Dobrowolski SF, Heintz C, Miller T, Ellingson C, Ellingson C, Ozer I, Gökçay G, Baykal T, Thöny B, Demirkol M, Blau N (2011) Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. Mol Genet Metab 102(2):116–121

    Article  PubMed  CAS  Google Scholar 

  • Du L, Damoiseaux R, Nahas SA et al (2009) Nonaminoglycoside compounds induce readthrough of nonsense mutations. J Exp Med 206:2285–2297

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Enns GM, Martinez DR, Kuzmin AI, Koch R, Wakeem CK, Woo SL, Eisensmith RC, Packman S (1999) Molecular correlations in phenylketonuria: mutation patterns and corresponding biochemical and clinical phenotypes in a heterogeneous California population. Pediatr Res 46(5):594–602

    Article  PubMed  CAS  Google Scholar 

  • Fiege B, Blau N (2007) Assessment of tetrahydrobiopterin responsiveness in phenylketonuria. J Pediatr 150:627–630

    Article  PubMed  CAS  Google Scholar 

  • Giannattasio S, Dianzani I, Lattanzio P, Spada M, Romano V, Calì F, Andria G, Ponzone A, Marra E, Piazza A (2001) Genetic heterogeneity in five Italian regions: analysis of PAH mutations and minihaplotypes. Hum Hered 52(3):154–159

    Article  PubMed  CAS  Google Scholar 

  • Guldberg P, Henriksen KF, Güttler F (1993) Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis. Genomics 17:141–146

    Article  PubMed  CAS  Google Scholar 

  • Guldberg P, Levy HL, Hanley WB, Koch R, Matalon R, Rouse BM, Trefz F, de la Cruz F, Henriksen KF, Güttler F (1996) Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study. Am J Hum Genet 59(1):84–94

    PubMed  CAS  PubMed Central  Google Scholar 

  • Güttler F, Azen C, Guldberg P et al (1999) Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the maternal phenylketonuria collaborative study. Pediatrics 104:258–262

    Article  PubMed  Google Scholar 

  • Hennermann JB, Bührer C, Blau N, Vetter B, Mönch E (2005) Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 86:S86–S90

    Article  PubMed  CAS  Google Scholar 

  • Ho G, Reichardt J, Christodoulou J (2013) In vitro read-through of phenylalanine hydroxylase (PAH) nonsense mutations using aminoglycosides: a potential therapy for phenylketonuria. J Inherit Metab Dis 36:955–959

    Article  PubMed  CAS  Google Scholar 

  • Howard M, Frizzell RA, Bedwell DM (1996) Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 2:467–469

    Article  PubMed  CAS  Google Scholar 

  • Karačić I, Mieili D, Sarnavka V et al (2009) Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab 97:165–171

    Article  PubMed  Google Scholar 

  • Kasnauskiene J, Giannattasio S, Lattanzio P, Cimbalistiene L, Kucinskas V (2003) The molecular basis of phenylketonuria in Lithuania. Hum Mutat 21:398

    Article  PubMed  CAS  Google Scholar 

  • Kayaalp E, Treacy E, Waters PJ, Byck S, Nowacki P, Scriver CR (1997) Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metaanalysis of genotype-phenotype correlations. Am J Hum Genet 61:309–317

    Article  Google Scholar 

  • Kim S-W, Jung J, Oh H-J et al (2006) Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene. Clin Chim Acta 365:279–287

    Article  PubMed  CAS  Google Scholar 

  • Kozak L, Hrabincova E, Kintr J et al (2006) Identification and characterization of large deletions in the phenylalanine hydroxylase (PAH) gene by MLPA: evidence for both homologous and non-homologous mechanisms of rearrangement. Mol Genet Metab 89:300–309

    Article  PubMed  CAS  Google Scholar 

  • Kure S, Hou D-C, Ohura T et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135:375–378

    Article  PubMed  CAS  Google Scholar 

  • Leandro J, Saraste J, Leandro P, Flatmark T (2011) The G46S-hPAH mutant protein: a model of study the rescue of aggregation-prone PKU mutations by chaperones. Mol Genet Metab 104:S40–S44

    Article  PubMed  CAS  Google Scholar 

  • Lee DH, Koo SK, Lee K-S et al (2004) The molecular basis of phenylketonuria in Koreans. J Hum Genet 49:617–621

    Article  PubMed  CAS  Google Scholar 

  • Leuzzi V, Carducci C, Carducci C et al (2006) The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency. J Inherit Metab Dis 29:38–46

    Article  PubMed  CAS  Google Scholar 

  • Lindner M, Haas D, Zschocke J, Burgard P (2001) Tetrahydrobiopterin responsiveness in phenylketonuria differs between patients with the same genotype. Mol Genet Metab 73:104–106

    Article  PubMed  CAS  Google Scholar 

  • Mallolas J, Vilaseca MA, Campistol J et al (1999) Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation. Hum Genet 105:468–473

    Article  PubMed  CAS  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Mitchell JJ, Wilcken B, Alexander I et al (2005) Tetrahydrobiopterin-responsive phenylketonuria: The New South Wales experience. Mol Genet Metab 86:S81–S85

    Article  PubMed  CAS  Google Scholar 

  • Muntau AC, Röschinger W, Habich M et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347:2122–2132

    Article  PubMed  CAS  Google Scholar 

  • Nudelman I, Glikin D, Smolkin B, Hainrichson M, Belakhov V, Baasov T (2010) Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of disease-causing nonsense mutations. Bioorg Med Chem 18:3735–3746

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell K, O’Neill C, Tighe O et al (2002) The mutation spectrum of hyperphenylalaninaemia in the Republic of Ireland: the population history of the Irish revisited. Eur J Hum Genet 10:530–538

    Article  PubMed  Google Scholar 

  • Pronina N, Giannattasio S, Lattanzio P, Lugovska R, Vevere P, Kornejeva A (2003) The molecular basis of phenylketonuria in Latvia. Hum Mutat 21:398–399

    Article  PubMed  CAS  Google Scholar 

  • Ramus SJ, Treacy EP, Cotton RGH (1995) Characterization of phenylalanine hydroxylase alleles in untreated phenylketonuria patients from Victoria, Australia: origin of alleles and haplotypes. Am J Hum Genet 56:1034–1041

    PubMed  CAS  PubMed Central  Google Scholar 

  • Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comput Biol 4:311–323

    Article  PubMed  CAS  Google Scholar 

  • Rozen S, Skaletsky HJ (2000) Primer3 on the WWW for general users and biological programmers. In: Krawetz S, Misener S (eds) Bioinformatics methods and protocols: methods in molecular biology. Humana Press, Totowa, pp 365–386

    Google Scholar 

  • Saunders CJ, Friez MJ, Patterson M, Nzabi M, Zhao W, Bi C (2010) Allele drop-out in the MECP2 gene due to G-quadruplex and i-motif sequences when using polymerase chain reaction-based diagnosis for Rett syndrome. Genet Test Mol Biomarkers 14:241–247

    Article  PubMed  CAS  Google Scholar 

  • Scriver CR, Hurtubise M, Konecki D et al (2003) PAHdb 2003: what a locus-specific knowledgebase can do. Hum Mutat 21:333–344

    Article  PubMed  CAS  Google Scholar 

  • Scriver CR, Kaufman S (2001) Hyperphenylalaniaemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS et al (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1667–1724

    Google Scholar 

  • Song F, Jin Y-W, Wang H, Zhang Y-M, Yang Y-L, Zhang T (2005) Mutations in exon 7 of the phenylalanine hydroxylase (PAH) gene in Chinese patients with phenylketonuria. Yichuan 27:53–56

    CAS  Google Scholar 

  • Tvedebrink T, Eriksen PS, Mogensen HS, Morling N (2009) Estimating the probability of allelic drop-out of STR alleles in forensic genetics. Forensic Sci Int Genet 3:222–226

    Article  PubMed  CAS  Google Scholar 

  • Wang L, Surendran S, Michals-Matalon K et al (2007) Mutations in the regulatory domain of phenylalanine hydroxylase and response to tetrahydrobiopterin. Genet Test 11:174–178

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Welch EM, Barton ER, Zhuo J et al (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447:87–91

    Article  PubMed  CAS  Google Scholar 

  • Woo SLC, Lidsky AS, Güttler F, Chandra T, Robson KJH (1983) Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature 306:151–155

    Article  PubMed  CAS  Google Scholar 

  • Zschocke J (2003) Phenylketonuria mutations in Europe. Hum Mutat 21:345–356

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This research was supported by donations from the NSW PKU Association and from the Rotary Club of Pennant Hills.

Author information

Authors and Affiliations

  1. Genetic Metabolic Disorders Research Unit, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia

    Gladys Ho & John Christodoulou

  2. Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, 2006, Australia

    Gladys Ho, Ian Alexander, Kaustuv Bhattacharya, Carolyn Ellaway, Bridget Wilcken & John Christodoulou

  3. Discipline of Genetic Medicine, University of Sydney, Sydney, NSW, 2006, Australia

    Ian Alexander, Kaustuv Bhattacharya, Carolyn Ellaway, Bridget Wilcken & John Christodoulou

  4. Genetic Metabolic Disorders Service, Western Sydney Genetics Program, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia

    Ian Alexander, Kaustuv Bhattacharya, Barbara Dennison, Carolyn Ellaway, Sue Thompson, Bridget Wilcken & John Christodoulou

  5. Dept of Nutrition and Dietetics, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia

    Barbara Dennison & Sue Thompson

Authors
  1. Gladys Ho
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  2. Ian Alexander
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  3. Kaustuv Bhattacharya
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  4. Barbara Dennison
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  5. Carolyn Ellaway
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  6. Sue Thompson
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  7. Bridget Wilcken
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  8. John Christodoulou
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Corresponding author

Correspondence to John Christodoulou .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. WSU Division of Health Sciences, Spokane, Washington, USA

    K. Michael Gibson

  3. Department of Biochemistry Genetics Unit, University of Oxford, Oxford, United Kingdom

    Garry Brown

  4. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  5. Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Nenad Blau, PhD

Appendices

Conflict of Interest

The authors declare no conflict of interest.

Synopsis

Mutation screening of a large cohort of phenylketonuria patients in Australia found a wide spectrum of mutations in this population, with a high proportion of patients likely to benefit from sapropterin treatment.

Compliance with Ethics Guidelines

Gladys Ho, Ian Alexander, Kaustuv Bhattacharya, Barbara Dennison, Carolyn Ellaway, Sue Thompson, Bridget Wilcken and John Christodoulou declare that they have no conflict of interest.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Details of Contributions of Individual Authors

GH

Design of experiments, implementation of experiments, data analysis and manuscript preparation

IA, KB, BD, CE, ST, BW, JC

Design of experiments, clinical information and manuscript preparation

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Ho, G. et al. (2013). The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 14. JIMD Reports, vol 14. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_284

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  • DOI: https://doi.org/10.1007/8904_2013_284

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