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Modified U1 snRNA and antisense oligonucleotides rescue splice mutations in SLC26A4 that cause hereditary hearing loss.
Lee, Byeonghyeon; Kim, Ye-Ri; Kim, Sang-Joo; Goh, Sung-Ho; Kim, Jong-Heun; Oh, Se-Kyung; Baek, Jeong-In; Kim, Un-Kyung; Lee, Kyu-Yup.
Afiliación
  • Lee B; Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • Kim YR; BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • Kim SJ; Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • Goh SH; BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • Kim JH; Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • Oh SK; BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • Baek JI; Therapeutic Target Discovery Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea.
  • Kim UK; Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • Lee KY; BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea.
Hum Mutat ; 40(8): 1172-1180, 2019 08.
Article en En | MEDLINE | ID: mdl-31033086
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ARN Nuclear Pequeño / Oligonucleótidos Antisentido / Transportadores de Sulfato / Pérdida Auditiva Sensorineural Límite: Humans Idioma: En Revista: Hum Mutat Asunto de la revista: GENETICA MEDICA Año: 2019 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: ARN Nuclear Pequeño / Oligonucleótidos Antisentido / Transportadores de Sulfato / Pérdida Auditiva Sensorineural Límite: Humans Idioma: En Revista: Hum Mutat Asunto de la revista: GENETICA MEDICA Año: 2019 Tipo del documento: Article