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Modified U1 snRNA and antisense oligonucleotides rescue splice mutations in SLC26A4 that cause hereditary hearing loss
- Source :
- Human Mutation.
- Publication Year :
- 2019
- Publisher :
- Hindawi Limited, 2019.
-
Abstract
- One of most important factors for messenger RNA (mRNA) transcription is the spliceosomal component U1 small nuclear RNA (snRNA), which recognizes 5' splicing donor sites at specific regions in pre-mRNA. Mutations in these sites disrupt U1 snRNA binding and cause abnormal splicing. In this study, we investigated mutations at splice sites in SLC26A4 (HGNC 8818), one of the major causative genes of hearing loss, which may result in the synthesis of abnormal pendrin, the channel protein encoded by the gene. Seventeen SLC26A4 variants with mutations in the U1 snRNA binding sites were assessed by minigene splicing assays, and 11 were found to result in abnormal splicing. Interestingly, eight of the 11 pathogenic mutations were intronic, suggesting the importance of conserved sequences at the intronic splice site. The application of modified U1 snRNA effectively rescued the abnormal splicing for most of these mutations. Although three were cryptic mutations, they were rescued by cotransfection of modified U1 snRNA and modified antisense oligonucleotides. Our results demonstrate the important role of snRNA in SLC26A4 mutations, suggesting the therapeutic potential of modified U1 snRNA and antisense oligonucleotides for neutralizing the pathogenic effect of the splice-site mutations that may result in hearing loss.
- Subjects :
- Hearing Loss, Sensorineural
Biology
U1 snRNA binding
Conserved sequence
03 medical and health sciences
Transcription (biology)
RNA, Small Nuclear
otorhinolaryngologic diseases
Genetics
Humans
splice
Gene
Conserved Sequence
Genetics (clinical)
030304 developmental biology
0303 health sciences
Binding Sites
Base Sequence
030305 genetics & heredity
Oligonucleotides, Antisense
Introns
Alternative Splicing
Sulfate Transporters
Mutation
RNA splicing
RNA Splice Sites
Small nuclear RNA
HeLa Cells
Minigene
Subjects
Details
- ISSN :
- 10981004 and 10597794
- Database :
- OpenAIRE
- Journal :
- Human Mutation
- Accession number :
- edsair.doi.dedup.....e3913df4e25f983f4e4e7ffe1e027b11