The loss of functional primary cilia is associated with many debilitating diseases including the blinding disease Leber congential amaurosis (LCA) and Joubert syndrome, which is the result of an underdeveloped cerebellum. Mutations in the gene encoding the 290 kDA centrosomal protein (CEP290) have been identified in both diseases; however, very little is known about CEP290 function. Theodore Drivas and colleagues at the University of Pennsylvania identified distinct domains of CEP290 that facilitate binding to cell membranes and microtubules. CEP290 activity was regulated by two autoinhibitory domains of the protein, which were critical for cilium formation. The authors determined that a previously described model of LCA, the rd16 mouse, produces a CEP290 protein lacking the microtubule-binding domain, and overexpression of two different truncated forms of CEP290 that lack the microtubule-binding domain resulted in localization to the cytosol. These data indicate that maintenance and regulation of both domains of this protein are required for proper localization and function. The above image is a composite fluorescence microscopy image of hTERT-RPE1 cells expressing truncations in CEP290 (GFP). Removal of the N-terminal microtubule-binding domain results in punctate staining, while removal of the cell membrane binding domain results in enhanced microtubule binding.
Mutations in the gene centrosomal protein 290 kDa (
Theodore G. Drivas, Erika L.F. Holzbaur, Jean Bennett