Alternative Splicing Shapes the Phenotype of a Mutation inBBS8To Cause Nonsyndromic Retinitis Pigmentosa

Abstract

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 ofBBS8exon 2A (IVS1-2A>G mutation) in theBBS8gene to photoreceptor cells. The IVS1-2A>G mutation leads to missplicing ofBBS8exon 2A, producing a frameshift in theBBS8reading frame and thus eliminating the protein specifically in photoreceptor cells. Cell types other than photoreceptors skip exon 2A from the matureBBS8transcript, which renders them immune to the mutation. We also show that the splicing ofBbs8exon 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.