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C. A. Murga-Zamalloa, R. A. Rachel, A. Swaroop, H. Khanna; Integrity and Ciliary Localization of the RPGR-SMC Protein Complex Are Critical for Normal Photoreceptor Function. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4796.
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Mutations in the cilia-centrosomal protein Retinitis Pigmentosa GTPase Regulator (RPGR) are associated with Retinitis Pigmentosa (X-linked and simplex), primary cilia dyskinesia, sperm dysfunction and hearing disorders. We previously showed that RPGR’s amino-terminal domain interacts with cohesin proteins Structural Maintenance of Chromosomes (SMC) 1 and SMC3 at the transition zone of photoreceptor primary cilia (Khanna et al., J Biol Chem, 2005; 280(39):33580-7). The present study was carried out to further elucidate the physiological role of the RPGR-SMC protein complex in the retina.
Co-immunoprecipitation assays were performed using wild-type and Rpgr-knock out mouse retinal extracts or transfected cell lines followed by immunoblotting. Immunofluorescence of retinal cryosections was carried out using standardized procedures.
We show that SMC1 exhibits light-dependent trafficking between the primary cilium and the outer nuclear layer. Moreover, the RPGR-SMC complex is disrupted in the Rpgr-knock out mouse retina, probably resulting in the mislocalization of the SMC proteins. CEP290, another RPGR-interacting protein, contains an SMC-like domain. Hence, we are also investigating the localization of SMC3 and SMC1 in the rd16 mouse, which carries an in-frame deletion in the myosin-tail domain of CEP290. Further studies are underway to examine the function of SMC proteins in photoreceptors and the effect of disease-causing mutations in RPGR on the integrity of the RPGR-SMC complex.
Our data suggest that RPGR regulates the nucleo-ciliary trafficking of SMC1 and SMC3 in primary cilia and disruption of the RPGR-SMC complex may underlie RPGR-associated retinal degeneration and syndromic ciliopathies.
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