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Therapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutations

2014-12-10Journal article Open access
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dc.contributor.authorMatos, Liliana
dc.contributor.authorCanals, Isaac
dc.contributor.authorDridi, Labri
dc.contributor.authorChoi, Yoo
dc.contributor.authorPrata, Maria Joâo
dc.contributor.authorJordan, Peter
dc.contributor.authorDesviat, Lourdes R.
dc.contributor.authorPerez, Belén
dc.contributor.authorPshezhetsky, A.V.
dc.contributor.authorGrinberg, Daniel
dc.contributor.authorAlves, Sandra
dc.contributor.authorVilageliu, Lluisa
dc.date.accessioned2016-02-17T17:49:20Z
dc.date.available2016-02-17T17:49:20Z
dc.date.issued2014-12-10
dc.description.abstractMutations affecting RNA splicing represent more than 20% of the mutant alleles in Sanfilippo syndrome type C, a rare lysosomal storage disorder that causes severe neurodegeneration. Many of these mutations are localized in the conserved donor or acceptor splice sites, while few are found in the nearby nucleotides. METHODS: In this study we tested several therapeutic approaches specifically designed for different splicing mutations depending on how the mutations affect mRNA processing. For three mutations that affect the donor site (c.234 + 1G > A, c.633 + 1G > A and c.1542 + 4dupA), different modified U1 snRNAs recognizing the mutated donor sites, have been developed in an attempt to rescue the normal splicing process. For another mutation that affects an acceptor splice site (c.372-2A > G) and gives rise to a protein lacking four amino acids, a competitive inhibitor of the HGSNAT protein, glucosamine, was tested as a pharmacological chaperone to correct the aberrant folding and to restore the normal trafficking of the protein to the lysosome. RESULTS: Partial correction of c.234 + 1G > A mutation was achieved with a modified U1 snRNA that completely matches the splice donor site suggesting that these molecules may have a therapeutic potential for some splicing mutations. Furthermore, the importance of the splice site sequence context is highlighted as a key factor in the success of this type of therapy. Additionally, glucosamine treatment resulted in an increase in the enzymatic activity, indicating a partial recovery of the correct folding. CONCLUSIONS: We have assayed two therapeutic strategies for different splicing mutations with promising results for the future applicationspt_PT
dc.description.sponsorshipFCT fellowship SFRH/BD/64592/2009 to LMpt_PT
dc.identifier.citationOrphanet J Rare Dis. 2014 Dec 10;9:180. doi: 10.1186/s13023-014-0180-ypt_PT
dc.identifier.doi10.1186/s13023-014-0180-ypt_PT
dc.identifier.issn1750-1172
dc.identifier.urihttp://hdl.handle.net/10400.18/3392
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherBioMed Central/ Orphanetpt_PT
dc.relation.publisherversionhttp://ojrd.biomedcentral.com/articles/10.1186/s13023-014-0180-ypt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectSplicingpt_PT
dc.subjectMutationpt_PT
dc.subjectLysosomal Storage Diseasept_PT
dc.titleTherapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutationspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage180pt_PT
oaire.citation.startPage180pt_PT
oaire.citation.titleOrphanet Journal of Rare Diseasespt_PT
oaire.citation.volume9pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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