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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2014

Autores

Matos L (Autor) Outra; Canals I (Autor) Outra; Dridi L (Autor) Outra; Choi Y (Autor) Outra; Maria João Ribeiro (Autor) FCUP; Jordan P (Autor) Outra; Pshezhetsky AV (Autor) Outra; Grinberg D (Autor) Outra; Alves S A (Autor) Outra; Vilageliu L (Autor) Outra

Revista

Título: Orphanet Journal of Rare Diseases

Vol. 9

Páginas: 1-180

ISSN: 1750-1172

Editora: Springer Nature

Indexação

ISI Web of Knowledge - 31 Citações

Scopus

Classificação Científica

CORDIS: Ciências da Saúde

FOS: Ciências médicas e da saúde

Outras Informações

ID Authenticus: P-00G-180

DOI: 10.1186/s13023-014-0180-y

Resumo (PT): .

Abstract (EN): Background: Mutations 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 applications.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Notas: .

Nº de páginas: 12