The blind leading the obese: the molecular pathophysiology of a human obesity syndrome

Abstract

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder affecting multiple organ systems and resulting in blindness, obesity, cognitive impairment, and congenital defects. Interest in the etiology of this disorder stems, in part, from the fact that patients with BBS develop common clinical problems, including obesity, diabetes and hypertension. Twelve genes independently causing BBS have been identified. The heterogeneity is explained by the existence of two BBS complexes, the BBSome consisting of seven known BBS proteins, and the BBS chaperone complex consisting of three known BBS proteins. The formation of the BBSome requires the function of the BBS chaperone complex. Both mouse and zebrafish data support a role for BBS genes in cilia function, and in intracellular and intraflagellar trafficking. From the work described here, a common primary function of BBS proteins has emerged, specifically the mediation and regulation of microtubule-based intracellular transport.

Fig. 1

Schematic drawing of the BBSome complex showing protein-protein interactions. BBS1, BBS2, BBS7 and BBS9 contain Beta-propeller repeats. BBS4 and BBS8 contain TPR repeats.

Fig. 2

Histological samples from control (left) and BBS knockout (right) mouse testes. Spermatozoa from BBS mice (Bbs4 knockout mouse shown) lack flagella.

Fig. 3

Histological slides of retina from eight month old wild-type (left) and Bbs4 knockout (right) mice. Note that Bbs4-/- mice lack the photoreceptor layer below the retinal pigmented epithelium (RPE). The photoreceptor layer has completely degenerated in these mice.

Fig. 4

BBS knockout mouse showing the obesity phenotype.

Fig. 5

BBS working model. Seven BBS proteins form a stable complex (BBSome) which localizes to centriolar satellites and to the membrane of cilia. BBSome components play a role in regulation of protein and vesicle trafficking to cilia, and perhaps to the plasma membrane. Chaperone-like BBS proteins (BBS6, BBS10 and BBS12) form a second BBS complex that is required for BBSome assembly.