TableEdit

Rachel, RA, May-Simera, HL, Veleri, S, Gotoh, N, Choi, BY, Murga-Zamalloa, C, McIntyre, JC, Marek, J, Lopez, I, Hackett, AN, Brooks, M, den Hollander, AI, Beales, PL, Li, T, Jacobson, SG, Sood, R, Martens, JR, Liu, P, Friedman, TB, Khanna, H, Koenekoop, RK, Kelley, MW and Swaroop, A (2012) Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis. J. Clin. Invest. 122:1233-45

Cilia are highly specialized microtubule-based organelles that have pivotal roles in numerous biological processes, including transducing sensory signals. Defects in cilia biogenesis and transport cause pleiotropic human ciliopathies. Mutations in over 30 different genes can lead to cilia defects, and complex interactions exist among ciliopathy-associated proteins. Mutations of the centrosomal protein 290 kDa (CEP290) lead to distinct clinical manifestations, including Leber congenital amaurosis (LCA), a hereditary cause of blindness due to photoreceptor degeneration. Mice homozygous for a mutant Cep290 allele (Cep290rd16 mice) exhibit LCA-like early-onset retinal degeneration that is caused by an in-frame deletion in the CEP290 protein. Here, we show that the domain deleted in the protein encoded by the Cep290rd16 allele directly interacts with another ciliopathy protein, MKKS. MKKS mutations identified in patients with the ciliopathy Bardet-Biedl syndrome disrupted this interaction. In zebrafish embryos, combined subminimal knockdown of mkks and cep290 produced sensory defects in the eye and inner ear. Intriguingly, combinations of Cep290rd16 and Mkksko alleles in mice led to improved ciliogenesis and sensory functions compared with those of either mutant alone. We propose that altered association of CEP290 and MKKS affects the integrity of multiprotein complexes at the cilia transition zone and basal body. Amelioration of the sensory phenotypes caused by specific mutations in one protein by removal of an interacting domain/protein suggests a possible novel approach for treating human ciliopathies.

PubMed PMC3314468 Online version:10.1172/JCI60981

Alleles; Amino Acid Sequence; Animals; Antigens, Neoplasm/genetics; Bardet-Biedl Syndrome/genetics; Chaperonins/deficiency; Chaperonins/genetics; Chaperonins/physiology; Cilia/ultrastructure; DNA Mutational Analysis; Ear/abnormalities; Ear/embryology; Eye Abnormalities/embryology; Eye Abnormalities/genetics; Gene Expression Regulation, Developmental; Genetic Complementation Test; Group II Chaperonins/deficiency; Group II Chaperonins/genetics; Group II Chaperonins/physiology; HEK293 Cells; Hair Cells, Auditory/ultrastructure; Humans; Leber Congenital Amaurosis/genetics; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins/deficiency; Microtubule-Associated Proteins/genetics; Microtubule-Associated Proteins/physiology; Molecular Sequence Data; Neoplasm Proteins/genetics; Nuclear Proteins/deficiency; Nuclear Proteins/genetics; Nuclear Proteins/physiology; Olfactory Receptor Neurons/ultrastructure; Photoreceptor Connecting Cilium/ultrastructure; Protein Interaction Mapping; Sensation Disorders/genetics; Sensation Disorders/pathology; Sensation Disorders/prevention & control; Sequence Alignment; Sequence Homology, Amino Acid; Zebrafish/embryology; Zebrafish/genetics; Zebrafish Proteins/deficiency; Zebrafish Proteins/genetics; Zebrafish Proteins/physiology