| Autor: |
Ya-Su Lyu, Pei-liang Shi, Xiao-Ling Chen, Yue-Xiao Tang, Yan-Fang Wang, Rong-Rong Liu, Xiao-Rui Luan, Yu Fang, Ru-Huan Mei, Zhen-Fang Du, Hai-Ping Ke, Erik Matro, Ling-En Li, Zhao-Yu Lin, Jing Zhao, Xiang Gao, Xian-Ning Zhang |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Nucleic Acids, Vol 5, Iss C (2016) |
| Druh dokumentu: |
article |
| ISSN: |
2162-2531 |
| DOI: |
10.1038/mtna.2016.17 |
| Popis: |
Epidermolytic palmoplantar keratoderma (EPPK) is a relatively common autosomal-dominant skin disorder caused by mutations in the keratin 9 gene (KRT9), with few therapeutic options for the affected so far. Here, we report a knock-in transgenic mouse model that carried a small insertion–deletion (indel) mutant of Krt9, c.434delAinsGGCT (p.Tyr144delinsTrpLeu), corresponding to the human mutation KRT9/c.500delAinsGGCT (p.Tyr167delinsTrpLeu), which resulted in a human EPPK-like phenotype in the weight-stress areas of the fore- and hind-paws of both Krt9+/mut and Krt9mut/mut mice. The phenotype confirmed that EPPK is a dominant-negative condition, such that mice heterozygotic for the K9-mutant allele (Krt9+/mut) showed a clear EPPK-like phenotype. Then, we developed a mutant-specific short hairpin RNA (shRNA) therapy for EPPK mice. Mutant-specific shRNAs were systematically identified in vitro using a luciferase reporter gene assay and delivered into Krt9+/mut mice. shRNA-mediated knockdown of mutant protein resulted in almost normal morphology and functions of the skin, whereas the same shRNA had a negligible effect in wild-type K9 mice. Our results suggest that EPPK can be treated by gene therapy, and this has significant implications for future clinical application. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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