TMEM107 in joubert Syndrome
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ABSTRACT:
PROVIDER: PRJEB11176 | ENA |
REPOSITORIES: ENA
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Project description:The primary cilium is a signaling organelle with a unique membrane composition maintained by a diffusional barrier residing at the transition zone. Many transition zone proteins, such as the tectonic complex, are linked to preserving ciliary composition; however, whether these proteins regulate active transport or physically impede membrane diffusion remains unknown. To understand tectonic’s role, we generated a photoreceptor specific Tctn1 knockout mouse. Loss of Tctn1 resulted in an absence of the entire tectonic complex yet had minimal effects on transition zone structure. Interestingly, we found that protein composition of the photoreceptor cilium was disrupted as non-resident membrane proteins accumulated in the cilium over time, ultimately resulting in photoreceptor degeneration. We further show that membrane proteins moved faster through the transition zone illustrating that the tectonic complex acts as a physical barrier to slow diffusion of membrane proteins so they can be properly sorted by ciliary transport carriers.
2023-10-24 | PXD042270 | Pride
Project description:We revealed the systematic regulation of ciliary composition in WT and the transition zone muntants.
2022-08-12 | PXD033090 | Pride
Project description:Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal dystrophy, intellectual disability, polydactyly, obesity and renal anomalies. In photoreceptors (PR), light sensation occurs in outer segments (OSs), which are specialized primary cilia. BBS1, the major BBS gene, is part of a protein complex called “BBSome”, which is involved in intracellular protein transport. However, the precise function of BBS1/BBSome in controlling trafficking of ciliary proteins in PRs remains unclear. To investigate the role of the BBSome in photoreceptors, we conducted a label free quantitative proteomic investigation on the protein contend of isolated adult mutant and control outer segments. We revealed that a Bbs1 KO results in the loss of the entire BBSome from OSs. Besides the loss of the BBSome we found an overall accumulation of non-outer segment proteins in the OS. A majority of these proteins were membrane-associated, supporting the role of BBS1/the BBSome in controlling ciliary transport of membrane-associated proteins.
2022-02-10 | PXD026646 | Pride
Project description:PFAPA, the syndrome of periodic fever associated with aphthous stomatitis, pharyngitis and/or cervical adenitis, is the most common periodic fever disease in children. Cases are mostly sporadic; the etiopathogenesis is unknown. In order to shed more insights into pathogenesis, we performed microarray expression analysis on samples from patients with PFAPA during and between flares, healthy controls and patients with hereditary autoinflammatory diseases during flares. RNA was extracted from whole peripheral blood from six patients with PFAPA syndrome during flares and asymptomatic intervals, six healthy controls and six patients with hereditary autoinflammatory diseases (2 familial Mediterranean fever (FMF), 1 TNF-receptor-asociated periodic fever syndrome (TRAPS) and 3 cryopyrin-associated periodic syndromes (CAPS)).
2011-06-20 | E-GEOD-17732 | biostudies-arrayexpress
Project description:The mechanisms of how highly conserved intraflagellar transport (IFT) protein complexes direct ciliary entry remain unknown. Exploring human ciliopathy genes, including monogenic obesity syndrome genes, has been a rich source of critical ciliary mechanisms. Using AP-MS purification of interactors of the CEP19 monogenic obesity gene, we identify factors and the first known mechanism for triggering ciliary entry of IFT complexes. CEP19 binds the CEP350 and FOP centriolar components and the highly conserved RABL2 GTPase. We discovered that the CEP19-RABL2 complex is first recruited by the centriolar CEP350/FOP complex, concurrently activates nucleotide exchange to capture and release intraflagellar transport B holocomplexes from a large centriolar pool to intraflagellar transport. The CEP19 network of interacting proteins regulates ciliary entry and ciliation, providing a new example of ciliary mechanisms deficient in monogenic obesity syndromes.
2017-06-21 | PXD006757 | Pride
Project description:Mutations in IQCB1/NPHP5 gene encoding the ciliary protein Nephrocystin 5 cause early-onset blinding disease Leber congenital amaurosis (LCA), together with kidney dysfunction in Senior-Løken Syndrome. For in vitro disease modeling, we obtained dermal fibroblasts from NPHP5-LCA patients, which were reprogrammed into induced pluripotent stem cells (iPSCs) and differentiated into retinal pigment epithelium (RPE) and retinal organoids. Patient fibroblasts and RPE demonstrated aberrantly elongated ciliary axonemes. Organoids revealed impaired development of outer segment structures, which are modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma. All patient-derived cells showed reduced levels of CEP290 protein, a critical cilia transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport. Disease phenotype in NPHP5-LCA retinal organoids could be rescued by AAV-mediated NPHP5 gene augmentation therapy. Our studies thus establish a human disease model and a path for treatment of NPHP5-LCA.
2022-08-26 | GSE200339 | GEO
Project description:Axonemal dynein ATPases direct eukaryotic ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here we describe a deficiency of CFAP45 in both humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar human ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45-/- mice is partially rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.
2020-11-05 | PXD019806 | Pride
Project description:Primary cilia are microtubule based sensory organelles that protrude from almost every cell type. Their membrane contains highly specialized receptors important for receiving and processing extracellular signals, which enables them to regulate several signalling pathways. A recently discovered characteristic is that cilia are also able to release extracellular vesicles (EVs) from the ciliary membrane. Since EVs have been shown to exert numerous functions in physiology and pathology, these findings have the potential to dramatically alter our understanding of how the primary cilium is able to regulate various signalling pathways in development and disease. In our study we focused on the release of EVs from a ciliated kidney cell line. Using control and mutant cell lines, in which ciliary trafficking was disrupted, we observed that loss of primary cilia function leads to altered EV secretion and composition in NTA (Nanoparticle Tracking Analysis) and Western blot. Cilia mutant cells released more small EVs compared to control, and their composition was also changed between mutant and control. Protein identification via mass spectrometry identified both cilia- as well as WNT signalling-associated proteins and miRNA sequencing determined WNT-related miRNAs, which were differentially expressed in small EVs isolated from the cilia mutant cell line. Because of the presence of differentially expressed WNT related molecules in these small EVs, we tested whether this would have an effect on the WNT activity of recipient cells. We observed that small EVs secreted from cilia mutant cells differentially modulated the WNT response in recipient cells compared to control. Our results highlight a possible new small EV-dependent ciliary signalling mechanism, since deficient primary cilia lead to a change in EV secretion, resulting in an altered signal transduction. These results provide us with new insights into ciliopathy disease pathogenesis.
2021-07-19 | GSE153227 | GEO
Project description:Ciliary margin zone cells have differential neurogenic potential in albino and pigmented eyes. We used single cell RNA sequencing (scRNA-seq) of albino and pigmented eyes to determine transcriptomic changes underlying differential RGC genesis.
2022-11-08 | GSE209764 | GEO
Project description:The Oscillation Zone (OZ) of unsynchronized roots was disected and divided into an upper (OZ2) and lower (OZ1) half . Samples were ordered according to DR5:GUS expression as analyzed by real time PCR to find periodic expression patterns
2010-09-12 | GSE21611 | GEO