Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis
| Autor: | Robert K. Koenekoop, Philip L. Beales, Jeremy C. McIntyre, Alice N. Hackett, Raman Sood, Shobi Veleri, Byung Yoon Choi, Carlos Murga-Zamalloa, Norimoto Gotoh, Samuel G. Jacobson, Rivka A. Rachel, Matthew Brooks, Anand Swaroop, Helen May-Simera, Thomas B. Friedman, Anneke I. den Hollander, Jeffrey R. Martens, Jonah E. Marek, Tiansen Li, Matthew W. Kelley, Irma Lopez, Hemant Khanna, Paul P. Liu |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Retinal degeneration
Genetics 0303 health sciences Cilium Sensory system General Medicine Biology medicine.disease Ciliopathies MKKS Cell biology 03 medical and health sciences Ciliopathy 0302 clinical medicine Bardet–Biedl syndrome Clinical investigation Ciliogenesis medicine Nuclear protein Allele Corrigendum Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Journal of Clinical Investigation, 122, 4, pp. 1233-45 Journal of Clinical Investigation, 122, 1233-45 |
| ISSN: | 0021-9738 |
| Popis: | Contains fulltext : 110598.pdf (Publisher’s version ) (Open Access) 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|