Purpose : To determine the retinal phenotype in mice with knockout of the Bbs10 gene, a component of the BBS/CCT chaperonin complex,and compare with mutation of Bbs1, a component of the BBSome.
Methods : A mouse model of Bardet Biedl Syndrome type 10 (BBS10) was developed by knocking out the Bbs10 gene. ERG, OCT,and visually guided swim assay (VGSA) natural history data were collected and were compared to WT and Bbs1M390R/M390R.
Results : Bbs10-/- mice initially weigh less than littermates (KO 7.2 gms vs WT 13.2 at P19) and are viable only with special feeding and husbandry. By 3 months Bbs10-/- are heavier (KO 32.1 gms vs WT 22.8, p=0.0149). ERG amplitudes are lower than WT by P19 (p=0.006) and VGSA is worse in the dark by 3.5 months (p= <0.0001),and in light by 9 months (p=<0.0001). At the earliest age tested, P21,there is no recordable 5 Hz flicker response in Bbs10-/-. Bbs1M390R/M390R are heavier than WT by 3 months (p=0.012) and have a recordable 5 Hz flicker until 6 months of age. At 6 months of age, Bbs10-/- mice have significantly worse ERG than Bbs1M390R/M390R in dark adapted 0.01(p=0.0001), Standard Combined Response (p=<0.0001) and Light Adapted 5 Hz flicker (p=0.0476). In the VGSA, Bbs10-/- had worse time to platform than Bbs1M390R/M390R in the 4-6 month dark swim (p=<0.0001) and 9-11 month both light (p=0.0186) and dark (p=<0.0001). On OCT at 2 months old ONL is equal in WT and Bbs10-/-(0.046 µm) but is 26% thinner in Bbs1M390R/M390R. By 6 months Bbs1M390R/M390R is 39% and Bbs10-/- is 13% of WT. WT ONL remained stable to 9 months.
Conclusions : Bbs10-/- mice eyes recapitulate retinal degeneration seen in human BBS10 and resemble retinal degeneration seen in Bbs1M390R/M390R with important differences: Bbs10-/- never develop a 5Hz flicker cone response, and have faster retinal degeneration overall. Our study correlates with recent human data suggesting BBS10 retinopathy is more severe and progresses faster than BBS1 (Heon et al.). Lack of 5 Hz flicker response in Bbs10-/- suggests an early role in cone function for BBS10.