期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 3, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mtna.2014.22
关键词
allele-specific; autosomal dominant inheritance; Co16a1; gene silencing; muscular dystrophy; siRNA
资金
- Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP [25-5]
- Research on Rare and intractable disease from the Ministry of Health, Labour and Welfare, Japan
- JSPS KAKENHI [23390236, 26293214]
- Grants-in-Aid for Scientific Research [26293214, 23390236] Funding Source: KAKEN
Ullrich congenital muscular dystrophy (UCMD) is an inherited muscle disorder characterized clinically by muscle weakness, distal joint hyperlaxity, and proximal joint contractures. Sporadic and recessive mutations in the three collagen VI genes, COL6A1, COL6A2, and COL6A3, are reported to be causative. In the sporadic forms, a heterozygous point mutation causing glycine substitution in the triple helical domain has been identified in higher rate. In this study, we examined the efficacy of siRNAs, which target point mutation site, on specific knockdown toward transcripts from mutant allele and evaluated consequent cellular phenotype of UCMD fibroblasts. We evaluated the effect of siRNAs targeted to silence-specific COL6A1 alleles in UCMD fibroblasts, where simultaneous expression of both wild-type and mutant collagen VI resulted in defective collagen localization. Addition of mutant-specific siRNAs allowed normal extracellular localization of collagen VI surrounding fibroblasts, suggesting selective inhibition of mutant collagen VI. Targeting the single-nucleotide COL6A1 c.850G>A (p.G284R) mutation responsible a sporadic autosomal dominant form of UCMD can potently and selectively block expression of mutant collagen VI. These results suggest that allele-specific knockdown of the mutant mRNA can potentially be considered as a therapeutic procedure in UCMD due to COL6A1 point mutations.
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