Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes.

Bardet-Biedl syndrome (BBS) is a heterogeneous disorder characterized by obesity, retinopathy, polydactyly, and congenital anomalies. The incidence of hypertension and diabetes are also increased in BBS patients. Mutation of 16 genes independently causes BBS, and seven BBS proteins form the BBSome that promotes ciliary membrane elongation. BBS3 (ARL6), an ADP ribosylation factor-like small GTPase, is not part of the BBSome complex. The in vivo function of BBS3 is largely unknown. Here we developed a Bbs3 knockout model and demonstrate that Bbs3(-/-) mice develop BBS-associated phenotypes, including retinal degeneration, male infertility, and increased body fat. Interestingly, Bbs3(-/-) mice develop some unique phenotypes not seen in other BBS knockout models: no overt obesity, severe hydrocephalus, and elevated blood pressure (shared by some but not all BBS gene knockout mice). We found that endogenous BBS3 and the BBSome physically interact and depend on each other for their ciliary localization. This finding explains the phenotypic similarity between Bbs3(-/-) mice and BBSome subunit knockout mice. Loss of Bbs3 does not affect BBSome formation but disrupts normal localization of melanin concentrating hormone receptor 1 to ciliary membranes and affects retrograde transport of Smoothened inside cilia. We also show that the endogenous BBSome and BBS3 associate with membranes and the membrane association of the BBSome and BBS3 are not interdependent. Differences between BBS mouse models suggest nonoverlapping functions to individual BBS protein.