Bardet-Biedl syndrome-8 (BBS8) protein is crucial for the development of outer segments in photoreceptor neurons

• Published in: Human molecular genetics 2018-01, Vol.27 (2), p.283-294
• Main Authors: Dilan, Tanya L, Singh, Ratnesh K, Saravanan, Thamaraiselvi, Moye, Abigail, Goldberg, Andrew F X, Stoilov, Peter, Ramamurthy, Visvanathan
• Format: Article
• Language: English
• Subjects: Animals; Bardet-Biedl Syndrome - genetics; Bardet-Biedl Syndrome - metabolism; Bardet-Biedl Syndrome - pathology; Cilia - metabolism; Disease Models, Animal; Mice; Mice, Knockout; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Neurons - metabolism; Neurons - pathology; Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - pathology; Retinal Rod Photoreceptor Cells - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddx399

Abstract Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by developmental abnormalities and vision loss. To date, mutations in 21 genes have been linked to BBS. The products of eight of these BBS genes form a stable octameric complex termed the BBSome. Mutations in BBS8, a component of the BBSome, cause early vision loss, but the role of BBS8 in supporting vision is not known. To understand the mechanisms by which BBS8 supports rod and cone photoreceptor function, we generated animal models lacking BBS8. The loss of BBS8 protein led to concomitant decrease in the levels of BBSome subunits, BBS2 and BBS5 and increase in the levels of the BBS1 and BBS4 subunits. BBS8 ablation was associated with severe reduction of rod and cone photoreceptor function and progressive degeneration of each photoreceptor subtype. We observed disorganized and shortened photoreceptor outer segments (OS) at post-natal day 10 as the OS elaborates. Interestingly, loss of BBS8 led to changes in the distribution of photoreceptor axonemal proteins and hyper-acetylation of ciliary microtubules. In contrast to properly localized phototransduction machinery, we observed OS accumulation of syntaxin3, a protein normally found in the cytoplasm and the synaptic termini. In conclusion, our studies demonstrate the requirement for BBS8 in early development and elaboration of ciliated photoreceptor OS, explaining the need for BBS8 in normal vision. The findings from our study also imply that early targeting of both rods and cones in BBS8 patients is crucial for successful restoration of vision.