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Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness
BACKGROUND: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024853/ https://www.ncbi.nlm.nih.gov/pubmed/26666653 http://dx.doi.org/10.1186/s13023-015-0375-x |
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author | Jeannesson-Thivisol, Elise Feillet, François Chéry, Céline Perrin, Pascal Battaglia-Hsu, Shyue-Fang Herbeth, Bernard Cano, Aline Barth, Magalie Fouilhoux, Alain Mention, Karine Labarthe, François Arnoux, Jean-Baptiste Maillot, François Lenaerts, Catherine Dumesnil, Cécile Wagner, Kathy Terral, Daniel Broué, Pierre de Parscau, Loïc Gay, Claire Kuster, Alice Bédu, Antoine Besson, Gérard Lamireau, Delphine Odent, Sylvie Masurel, Alice Guéant, Jean-Louis Namour, Fares |
author_facet | Jeannesson-Thivisol, Elise Feillet, François Chéry, Céline Perrin, Pascal Battaglia-Hsu, Shyue-Fang Herbeth, Bernard Cano, Aline Barth, Magalie Fouilhoux, Alain Mention, Karine Labarthe, François Arnoux, Jean-Baptiste Maillot, François Lenaerts, Catherine Dumesnil, Cécile Wagner, Kathy Terral, Daniel Broué, Pierre de Parscau, Loïc Gay, Claire Kuster, Alice Bédu, Antoine Besson, Gérard Lamireau, Delphine Odent, Sylvie Masurel, Alice Guéant, Jean-Louis Namour, Fares |
author_sort | Jeannesson-Thivisol, Elise |
collection | PubMed |
description | BACKGROUND: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations. METHODS: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. RESULTS: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response. CONCLUSIONS: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0375-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5024853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-50248532016-09-20 Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness Jeannesson-Thivisol, Elise Feillet, François Chéry, Céline Perrin, Pascal Battaglia-Hsu, Shyue-Fang Herbeth, Bernard Cano, Aline Barth, Magalie Fouilhoux, Alain Mention, Karine Labarthe, François Arnoux, Jean-Baptiste Maillot, François Lenaerts, Catherine Dumesnil, Cécile Wagner, Kathy Terral, Daniel Broué, Pierre de Parscau, Loïc Gay, Claire Kuster, Alice Bédu, Antoine Besson, Gérard Lamireau, Delphine Odent, Sylvie Masurel, Alice Guéant, Jean-Louis Namour, Fares Orphanet J Rare Dis Research BACKGROUND: Mutations in Phenylalanine Hydroxylase (PAH) gene cause phenylketonuria. Sapropterin (BH4), the enzyme cofactor, is an important therapeutical strategy in phenylketonuria. However, PAH is a highly polymorphic gene and it is difficult to identify BH4-responsive genotypes. We seek here to improve prediction of BH4-responsiveness through comparison of genotypes, BH4-loading test, predictions of responsiveness according to the literature and types and locations of mutations. METHODS: A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria, benefited from a 24-hour BH4-loading test and had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. RESULTS: Overall, 31.6 % of patients were BH4-responsive. The number of different mutations found was 127, including 26 new mutations. The mutations c.434A > T, c.500A > T, c.529G > C, c.1045 T > G and c.1196 T > C were newly classified as being BH4-responsive. We identified 261 genotypes, among which 46 were newly recognized as being BH4-responsive. Even though patients carry 2 responsive alleles, BH4-responsiveness cannot be predicted with certainty unless they present mild hyperphenylalaninemia. BH4-responsiveness cannot be predicted in patients carrying one responsive mutation only. In general, the milder the phenotype is, the stronger the BH4-response is. Almost exclusively missense mutations, particularly in exons 12, 11 and 8, are associated with BH4-responsiveness and any other type of mutation predicts a negative response. CONCLUSIONS: This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations. As others, it highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13023-015-0375-x) contains supplementary material, which is available to authorized users. BioMed Central 2015-12-15 /pmc/articles/PMC5024853/ /pubmed/26666653 http://dx.doi.org/10.1186/s13023-015-0375-x Text en © Jeannesson-Thivisol et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Jeannesson-Thivisol, Elise Feillet, François Chéry, Céline Perrin, Pascal Battaglia-Hsu, Shyue-Fang Herbeth, Bernard Cano, Aline Barth, Magalie Fouilhoux, Alain Mention, Karine Labarthe, François Arnoux, Jean-Baptiste Maillot, François Lenaerts, Catherine Dumesnil, Cécile Wagner, Kathy Terral, Daniel Broué, Pierre de Parscau, Loïc Gay, Claire Kuster, Alice Bédu, Antoine Besson, Gérard Lamireau, Delphine Odent, Sylvie Masurel, Alice Guéant, Jean-Louis Namour, Fares Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness |
title | Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness |
title_full | Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness |
title_fullStr | Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness |
title_full_unstemmed | Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness |
title_short | Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness |
title_sort | genotype-phenotype associations in french patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024853/ https://www.ncbi.nlm.nih.gov/pubmed/26666653 http://dx.doi.org/10.1186/s13023-015-0375-x |
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