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Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier

Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to resu...

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Autores principales: Hinzpeter, Alexandre, Aissat, Abdel, Sondo, Elvira, Costa, Catherine, Arous, Nicole, Gameiro, Christine, Martin, Natacha, Tarze, Agathe, Weiss, Laurence, de Becdelièvre, Alix, Costes, Bruno, Goossens, Michel, Galietta, Luis J., Girodon, Emmanuelle, Fanen, Pascale
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951375/
https://www.ncbi.nlm.nih.gov/pubmed/20949073
http://dx.doi.org/10.1371/journal.pgen.1001153
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author Hinzpeter, Alexandre
Aissat, Abdel
Sondo, Elvira
Costa, Catherine
Arous, Nicole
Gameiro, Christine
Martin, Natacha
Tarze, Agathe
Weiss, Laurence
de Becdelièvre, Alix
Costes, Bruno
Goossens, Michel
Galietta, Luis J.
Girodon, Emmanuelle
Fanen, Pascale
author_facet Hinzpeter, Alexandre
Aissat, Abdel
Sondo, Elvira
Costa, Catherine
Arous, Nicole
Gameiro, Christine
Martin, Natacha
Tarze, Agathe
Weiss, Laurence
de Becdelièvre, Alix
Costes, Bruno
Goossens, Michel
Galietta, Luis J.
Girodon, Emmanuelle
Fanen, Pascale
author_sort Hinzpeter, Alexandre
collection PubMed
description Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies.
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spelling pubmed-29513752010-10-14 Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier Hinzpeter, Alexandre Aissat, Abdel Sondo, Elvira Costa, Catherine Arous, Nicole Gameiro, Christine Martin, Natacha Tarze, Agathe Weiss, Laurence de Becdelièvre, Alix Costes, Bruno Goossens, Michel Galietta, Luis J. Girodon, Emmanuelle Fanen, Pascale PLoS Genet Research Article Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies. Public Library of Science 2010-10-07 /pmc/articles/PMC2951375/ /pubmed/20949073 http://dx.doi.org/10.1371/journal.pgen.1001153 Text en Hinzpeter et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hinzpeter, Alexandre
Aissat, Abdel
Sondo, Elvira
Costa, Catherine
Arous, Nicole
Gameiro, Christine
Martin, Natacha
Tarze, Agathe
Weiss, Laurence
de Becdelièvre, Alix
Costes, Bruno
Goossens, Michel
Galietta, Luis J.
Girodon, Emmanuelle
Fanen, Pascale
Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier
title Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier
title_full Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier
title_fullStr Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier
title_full_unstemmed Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier
title_short Alternative Splicing at a NAGNAG Acceptor Site as a Novel Phenotype Modifier
title_sort alternative splicing at a nagnag acceptor site as a novel phenotype modifier
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951375/
https://www.ncbi.nlm.nih.gov/pubmed/20949073
http://dx.doi.org/10.1371/journal.pgen.1001153
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