Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/124374
COMPARTIR / EXPORTAR:
logo share SHARE logo core CORE BASE
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE

Invitar a revisión por pares abierta
Título

Functional characterization of the spf/ash splicing variation in OTC deficiency of mice and man

AutorRivera-Barahona, Ana CSIC; Sánchez-Alcudia, Rocío CSIC; Viecelli, Hiu Man; Rüefenacht, Veronique; Pérez, Belén CSIC ORCID; Ugarte, Magdalena CSIC ; Häberle, Johannes; Thöny, Beat; Desviat, Lourdes R. CSIC ORCID
Fecha de publicación8-abr-2015
EditorPublic Library of Science
CitaciónPLoS ONE 10(4): e0122966 (2015)
ResumenThe spf/ash mouse model of ornithine transcarbamylase (OTC) deficiency, a severe urea cycle disorder, is caused by a mutation (c.386G>A; p.R129H) in the last nucleotide of exon 4 of the Otc gene, affecting the 5' splice site and resulting in partial use of a cryptic splice site 48 bp into the adjacent intron. The equivalent nucleotide change and predicted amino acid change is found in OTC deficient patients. Here we have used liver tissue and minigene assays to dissect the transcriptional profile resulting from the >spf/ash> mutation in mice and man. For the mutant mouse, we confirmed liver transcripts corresponding to partial intron 4 retention by the use of the c.386+48 cryptic site and to normally spliced transcripts, with exon 4 always containing the c.386G>A (p.R129H) variant. In contrast, the OTC patient exhibited exon 4 skipping or c.386G>A (p.R129H)-variant exon 4 retention by using the natural or a cryptic splice site at nucleotide position c.386+4. The corresponding OTC tissue enzyme activities were between 3-6% of normal control in mouse and human liver. The use of the cryptic splice sites was reproduced in minigenes carrying murine or human mutant sequences. Some normally spliced transcripts could be detected in minigenes in both cases. Antisense oligonucleotides designed to block the murine cryptic +48 site were used in minigenes in an attempt to redirect splicing to the natural site. The results highlight the relevance of in depth investigations of the molecular mechanisms of splicing mutations and potential therapeutic approaches. Notably, they emphasize the fact that findings in animal models may not be applicable for human patients due to the different genomic context of the mutations.
URIhttp://hdl.handle.net/10261/124374
DOI10.1371/journal.pone.0122966
Identificadoresdoi: 10.1371/journal.pone.0122966
issn: 1932-6203
Aparece en las colecciones: (CBM) Artículos




Ficheros en este ítem:
Fichero Descripción Tamaño Formato
Desviat RL Fuctional Caracterization.pdf862,92 kBAdobe PDFVista previa
Visualizar/Abrir
Mostrar el registro completo

CORE Recommender

PubMed Central
Citations

10
checked on 27-mar-2024

SCOPUSTM   
Citations

17
checked on 25-mar-2024

WEB OF SCIENCETM
Citations

14
checked on 26-feb-2024

Page view(s)

269
checked on 27-mar-2024

Download(s)

189
checked on 27-mar-2024

Google ScholarTM

Check

Altmetric

Altmetric


Artículos relacionados:


NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.