{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Takita S"],"funding":["NEI NIH HHS","National Eye Institute","Research to Prevent Blindness","School of Medicine, Indiana University","National Institutes of Health","NIH HHS"],"pagination":["e23606"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11047207"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["38(8)"],"pubmed_abstract":["Rhodopsin mislocalization encompasses various blind conditions. Rhodopsin mislocalization is the primary factor leading to rod photoreceptor dysfunction and degeneration in autosomal dominant retinitis pigmentosa (adRP) caused by class I mutations. In this study, we report a new knock-in mouse model that harbors a class I Q344X mutation in the endogenous rhodopsin gene, which causes rod photoreceptor degeneration in an autosomal dominant pattern. In Rho<sup>Q344X/+</sup> mice, mRNA transcripts from the wild-type (Rho) and Rho<sup>Q344X</sup> mutant rhodopsin alleles are expressed at equal levels. However, the amount of RHO<sup>Q344X</sup> mutant protein is 2.7 times lower than that of wild-type rhodopsin, a finding consistent with the rapid degradation of the mutant protein. Immunofluorescence microscopy indicates that RHO<sup>Q344X</sup> is mislocalized to the inner segment and outer nuclear layers of rod photoreceptors in both Rho<sup>Q344X/+</sup> and Rho<sup>Q344X/Q344X</sup> mice, confirming the essential role of the C-terminal VxPx motif in promoting OS delivery of rhodopsin. The mislocalization of RHO<sup>Q344X</sup> is associated with the concurrent mislocalization of wild-type rhodopsin in Rho<sup>Q344X/+</sup> mice. To understand the global changes in proteostasis, we conducted quantitative proteomics analysis and found attenuated expression of rod-specific OS membrane proteins accompanying reduced expression of ciliopathy causative gene products, including constituents of BBSome and axonemal dynein subunit. Those studies unveil a novel negative feedback regulation involving ciliopathy-associated proteins. In this process, a defect in the trafficking signal leads to a reduced quantity of the trafficking apparatus, culminating in a widespread reduction in the transport of ciliary proteins."],"journal":["FASEB journal : official publication of the Federation of American Societies for Experimental Biology"],"pubmed_title":["Rhodopsin mislocalization drives ciliary dysregulation in a novel autosomal dominant retinitis pigmentosa knock-in mouse model."],"pmcid":["PMC11047207"],"funding_grant_id":["R01EY029680","R01 EY028884","R01EY028884","R01 EY029680","S10 OD023436"],"pubmed_authors":["Mann RJ","Imanishi Y","LePage D","Conlon RA","Takita S","S Imanishi S","Miyagi M","Harikrishnan H","Jahan S"],"additional_accession":[]},"is_claimable":false,"name":"Rhodopsin mislocalization drives ciliary dysregulation in a novel autosomal dominant retinitis pigmentosa knock-in mouse model.","description":"Rhodopsin mislocalization encompasses various blind conditions. Rhodopsin mislocalization is the primary factor leading to rod photoreceptor dysfunction and degeneration in autosomal dominant retinitis pigmentosa (adRP) caused by class I mutations. In this study, we report a new knock-in mouse model that harbors a class I Q344X mutation in the endogenous rhodopsin gene, which causes rod photoreceptor degeneration in an autosomal dominant pattern. In Rho<sup>Q344X/+</sup> mice, mRNA transcripts from the wild-type (Rho) and Rho<sup>Q344X</sup> mutant rhodopsin alleles are expressed at equal levels. However, the amount of RHO<sup>Q344X</sup> mutant protein is 2.7 times lower than that of wild-type rhodopsin, a finding consistent with the rapid degradation of the mutant protein. Immunofluorescence microscopy indicates that RHO<sup>Q344X</sup> is mislocalized to the inner segment and outer nuclear layers of rod photoreceptors in both Rho<sup>Q344X/+</sup> and Rho<sup>Q344X/Q344X</sup> mice, confirming the essential role of the C-terminal VxPx motif in promoting OS delivery of rhodopsin. The mislocalization of RHO<sup>Q344X</sup> is associated with the concurrent mislocalization of wild-type rhodopsin in Rho<sup>Q344X/+</sup> mice. To understand the global changes in proteostasis, we conducted quantitative proteomics analysis and found attenuated expression of rod-specific OS membrane proteins accompanying reduced expression of ciliopathy causative gene products, including constituents of BBSome and axonemal dynein subunit. Those studies unveil a novel negative feedback regulation involving ciliopathy-associated proteins. In this process, a defect in the trafficking signal leads to a reduced quantity of the trafficking apparatus, culminating in a widespread reduction in the transport of ciliary proteins.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2026-06-01T10:17:13.199Z","creation":"2025-07-10T03:09:09.294Z"},"accession":"S-EPMC11047207","cross_references":{"pubmed":["38648465"],"doi":["10.1096/fj.202302260RR","10.1096/fj.202302260rr"]}}