Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable: Molecular pathology of mutations in PAH exon 11

Molecular Genetics and Metabolism

Volumn 106, Issue 4, 2012, Pages 403-411

  Heintz, Caroline ^a   Dobrowolski, Steven F ^b   Andersen, Henriette Skovgaard ^c   Demirkol, Mübeccel ^d   Blau, Nenad ^a,e,f,g   Andresen, Brage Storstein ^c  

^a UNIVERSITY CHILDREN S HOSPITAL   (Switzerland)

^b UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^d ISTANBUL UNIVERSITY   (Turkey)

^e UNIVERSITY OF ZURICH   (Switzerland)

^f Research Center for Children RCC   (Switzerland)

^g UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

Author keywords

Exomic splicing enhancer; Hyperphenylalaninemia; MRNA splicing; Phenylketonuria; Pseudoexon; Tetrahydrobiopterin

Indexed keywords

CYCLOHEXIMIDE; PHENYLALANINE 4 MONOOXYGENASE; TETRAHYDROBIOPTERIN;

ARTICLE; CONTROLLED STUDY; EXON; GENOTYPE; HUMAN; HUMAN CELL; HUMAN TISSUE; INTRON; LYMPHOBLAST; LYMPHOID CELL LINE; MOLECULAR PATHOLOGY; MUTATION; PHENOTYPE; PRIORITY JOURNAL; PROTEIN MOTIF; RNA PROCESSING;

ALTERNATIVE SPLICING; ANIMALS; BASE SEQUENCE; CELL LINE; CHROMATOGRAPHY, AFFINITY; ENTROPY; EXONS; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MOLECULAR SEQUENCE DATA; MUTAGENESIS; MUTATION; NUCLEAR PROTEINS; PATHOLOGY, MOLECULAR; PHENYLALANINE HYDROXYLASE; PHENYLKETONURIAS; REPRODUCIBILITY OF RESULTS; RNA PRECURSORS; RNA SPLICE SITES; RNA-BINDING PROTEINS; TRANSFECTION;

EID: 84864364258     PISSN: 10967192     EISSN: 10967206     Source Type: Journal    
DOI: 10.1016/j.ymgme.2012.05.013     Document Type: Article

References (27)

1. Blau N., Van Spronsen F.J., Levy H.L. Phenylketonuria. Lancet 2010, 376:1417-1427.
2. Kaufman S. New tetrahydrobiopterin-dependent systems. Annu. Rev. Nutr. 1993, 13:261-286.
3. Scriver C.R., Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. The Metabolic and Molecular Bases of Inherited Disease 2001, 1667-1724. McGraw-Hill, New York. C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle, B. Childs, B. Vogelstein (Eds.).
4. Scriver C.R. The PAH gene, phenylketonuria, and a paradigm shift. Hum. Mutat. 2007, 28:831-845.
5. Pey A.L., Stricher F., Serrano L., Martinez A. Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Am. J. Hum. Genet. 2007, 81:1006-1024.
6. Pagani F., Baralle F.E. Genomic variants in exons and introns: identifying the splicing spoilers. Nat. Rev. Genet. 2004, 5:389-396.
7. Blau N. Sapropterin dihydrochloride for phenylketonuria and tetrahydrobiopterin deficiency. Expert Rev. Endocrinol. Metab. 2010, 5:483-494.
8. Muntau A.C., Röschinger W., Habich M., Demmelmair H., Hoffmann B., Sommerhoff C.P., Roscher A.A. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N. Engl. J. Med. 2002, 347:2122-2132.
9. Karacic I., Meili D., Sarnavka V., Heintz C., Thony B., Ramadza D.P., Fumic K., Mardesic D., Baric I., Blau N. Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol. Genet. Metab. 2009, 97:165-171.
10. Dobrowolski S.F., Heintz C., Miller T., Ellingson C.R., Ellingson C.C., Özer I., Gökcay G., Baykal T., Thöny B., Demirkol M., Blau N. Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin-responsiveness in Turkish PKU population. Mol. Genet. Metab. 2011, 10:116-121.
11. Trefz F.K., Scheible D., Gotz H., Frauendienst-Egger G. Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria. J. Inherit. Metab. Dis. 2009, 32:22-26.
12. Andersen B.S., Krainer A.R. When the genetic code is not enough - how sequence variations can affect pre-mRNA splicing and cause (complex) disease. Genetics of Complex Human Diseases 2009, 165-182. Cold Spring Harbor Laboratory Press, New York. L. Almasy, A. Al-Chalabi (Eds.).
13. Ellingsen S., Knappskog P.M., Eiken H.G. Phenylketonuria splice mutation (EXON6nt-96A->g) masquerading as missense mutation (Y204C). Hum. Mutat. 1997, 9:88-90.
14. Chao H.K., Hsiao K.J., Su T.S. A silent mutation induces exon skipping in the phenylalanine hydroxylase gene in phenylketonuria. Hum. Genet. 2001, 108:14-19.
15. Dobrowolski S.F., Andersen H.S., Doktor T.K., Andresen B.S. The phenylalanine hydroxylase c.30C>G synonymous variation (p.G10G) creates a common exonic splicing silencer. Mol. Genet. Metab. 2010, 100:316-323.
16. Brickell P.M. Immortalization of human B-lymphocytes by Epstein-Barr virus. Methods Mol. Biol. 1992, 8:213-218.
17. Nielsen K.B., Sorensen S., Cartegni L., Corydon T.J., Doktor T.K., Schroeder L.D., Reinert L.S., Elpeleg O., Krainer A.R., Gregersen N., Kjems J., Andresen B.S. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am. J. Hum. Genet. 2007, 80:416-432.
18. Abadie V., Jaruzelska J., Lyonnet S., Millasseau P., Berthelon M., Rey F., Munnich A., Rey J. Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria. Hum. Mol. Genet. 1993, 2:31-34.
19. Heintz C., Troxler H., Martinez A., Thöny B., Blau N. Quantification of phenylalanine hydroxylase activity by isotope-dilution liquid chromatography-electrospray ionization tandem mass spectrometry. Mol. Genet. Metab. 2012, 105:559-565.
20. Watanabe N., Kamei S., Ohkubo A., Yamanaka M., Ohsawa S., Makino K., Tokuda K. Urinary protein as measured with a pyrogallol red-molybdate complex, manually and in a Hitachi 726 automated analyzer. Clin. Chem. 1986, 32:1551-1554.
21. Hwang J., Maquat L.E. Nonsense-mediated mRNA decay (NMD) in animal embryogenesis: to die or not to die, that is the question. Curr. Opin. Genet. Dev. 2011, 21:422-430.
22. Jaruzelska J., Abadie V., d'Aubenton-Carafa Y., Brody E., Munnich A., Marie J. In vitro splicing deficiency induced by a C to T mutation at position -3 in the intron 10 acceptor site of the phenylalanine hydroxylase gene in a patient with phenylketonuria. J. Biol. Chem. 1995, 270:20370-20375.
23. Goren A., Ram O., Amit M., Keren H., Lev-Maor G., Vig I., Pupko T., Ast G. Comparative analysis identifies exonic splicing regulatory sequences-The complex definition of enhancers and silencers. Mol. Cell 2006, 22:769-781.
24. Tournier I., Vezain M., Martins A., Charbonnier F., Baert-Desurmont S., Olschwang S., Wang Q., Buisine M.P., Soret J., Tazi J., Frebourg T., Tosi M. A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum. Mutat. 2008, 29:1412-1424.
25. Daniele A., Cardillo G., Pennino C., Carbone M.T., Scognamiglio D., Esposito L., Correra A., Castaldo G., Zagari A., Salvatore F. Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants. Biochim. Biophys. Acta 2008, 1782:378-384.
26. Desviat L.R., Pérez B., Bèlanger-Quintana A., Castro M., Aguado C., Sánchez A., García M.J., Martínez-Pardo M., Ugarte M. Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype. Mol. Genet. Metab. 2004, 82:157-162.
27. Hofmann M.H., Blievernicht J.K., Klein K., Saussele T., Schaeffeler E., Schwab M., Zanger U.M. Aberrant splicing caused by single nucleotide polymorphism c.516G>T [Q172H], a marker of CYP2B6*6, is responsible for decreased expression and activity of CYP2B6 in liver. J. Pharmacol. Exp. Ther. 2008, 325:284-292.