期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 35, 期 10, 页码 1860-1870出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00040-15
关键词
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资金
- Mary Babb Randolph Cancer Center
- NIH grant [P20 RR016440, P30 GM103488, P20 GM103434]
- National Institutes of Health [EY017035]
- West Virginia Lions
- Lions Club International Fund
- West Virginia University
Bardet-Biedl syndrome (BBS) is a genetic disorder affecting multiple systems and organs in the body. Several mutations in genes associated with BBS affect only photoreceptor cells and cause nonsyndromic retinitis pigmentosa (RP), raising the issue of why certain mutations manifest as a systemic disorder whereas other changes in the same gene affect only a specific cell type. Here, we show that cell-type-specific alternative splicing is responsible for confining the phenotype of the A-to-G substitution in the 3' splice site of BBS8 exon 2A (IVS1-2A>G mutation) in the BBS8 gene to photoreceptor cells. The IVS1-2A>G mutation leads to missplicing of BBS8 exon 2A, producing a frameshift in the BBS8 reading frame and thus eliminating the protein specifically in photoreceptor cells. Cell types other than photoreceptors skip exon 2A from the mature BBS8 transcript, which renders them immune to the mutation. We also show that the splicing of Bbs8 exon 2A in photoreceptors is directed exclusively by redundant splicing enhancers located in the adjacent introns. These intronic sequences are sufficient for photoreceptor-cell-specific splicing of heterologous exons, including an exon with a randomized sequence.
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