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

• Type: Article in International Scientific Journal
• Date: 2014

Authors

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

Journal

Title: Orphanet Journal of Rare Diseases

Vol. 9

Pages: 1-180

ISSN: 1750-1172

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 31 Citations

Scopus

Scientific classification

CORDIS: Health sciences

FOS: Medical and Health sciences

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

Notes: .

No. of pages: 12