Ccdc66 null mutation causes retinal degeneration and dysfunction

Gerding, Wanda M.; Schreiber, S.; Schulte-Middelmann, Tobias; Marques, António; Atorf, Jenny; Akkad, Denis A.; Dekomien, Gabriele; Kremers, Jan; Dermietzel, Rolf; Gal, Andreas; Rülicke, Thomas; Ibrahim, Saleh M.; Epplen, Jörg T.; Petrasch‐Parwez, Elisabeth

doi:10.1093/hmg/ddr282

Cited by 38 publications

(56 citation statements)

References 25 publications

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“…CCDC66 point mutation in dogs and null mutations in mouse were previously implicated in retinal degeneration, a phenotype that is common to ciliopathies (Dekomien et al, 2010;Gerding et al, 2011). We first identified CCDC66 as a proximity partner for known centriolar satellite proteins including CEP72, which interacts with CEP290 and functions in cilium formation and ciliary targeting of the BBSome complex (Stowe et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Given the possible role of CCDC66 in ciliary trafficking, perturbation of this function could lead to photoreceptor degeneration through mislocalization of proteins required for phototransduction. Previous studies reported localization of CCDC66 to the inner segments of photoreceptor cells (Dekomien et al, 2010) and to the outer segment of rod cells (Gerding et al, 2011). Higher resolution localization studies in photoreceptor cells are required to determine whether the localization of to the centrosome and cilium complex and/or microtubules in RPE1 cells reflects localization in photoreceptor cells.…”

Section: Research Articlementioning

confidence: 99%

“…The CEP72 BioID hits also include proteins that were not previously implicated in ciliogenesis. Among these hits is the retinal degeneration gene CCDC66 (Dekomien et al, 2010;Gerding et al, 2011). CCDC66 has been reported to localize to centriolar satellites (Gupta et al, 2015) and its mRNA has been found to interact with microtubules in a screen for microtubule-binding transcripts in Xenopus laevis egg extracts (Sharp et al, 2011).…”

Section: Proximity Mapping Identifies New Centriolar Satellite Proteinsmentioning

confidence: 99%

“…A homozygous mutation in the CCDC66 gene was shown to cause autosomal recessively inherited, generalized progressive retinal atrophy, the canine counterpart of Retinitis pigmentosa (Dekomien et al, 2010). Moreover, CCDC66 knockout in mouse leads to early photoreceptor degeneration, with a slow, progressive retinal phenotype and physiological impairment of the retina (Gerding et al, 2011). These studies together suggest an important role for CCDC66 in retinal development and function.…”

Section: Introductionmentioning

confidence: 96%

“…The interactors identified by this map include both known satellite proteins and previously uncharacterized proteins (Firat-Karalar et al, 2014). Among these proteins, we chose CCDC66, for further study, because it has been previously implicated in microtubule-mediated functions, including spindle pole and centriolar satellite organization (Gupta et al, 2015;Sharp et al, 2011), and its link to retinal degeneration (Dekomien et al, 2010;Gerding et al, 2011). A homozygous mutation in the CCDC66 gene was shown to cause autosomal recessively inherited, generalized progressive retinal atrophy, the canine counterpart of Retinitis pigmentosa (Dekomien et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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The centriolar satellite protein CCDC66 interacts with CEP290 and functions in cilium formation and trafficking

Conkar

Culfa

Odabasi

et al. 2017

Journal of Cell Science

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Centriolar satellites are membrane-less structures that localize and move around the centrosome and cilium complex in a microtubuledependent manner. They play important roles in centrosome-and cilium-related processes, including protein trafficking to the centrosome and cilium complex, and ciliogenesis, and they are implicated in ciliopathies. Despite the important regulatory roles of centriolar satellites in the assembly and function of the centrosome and cilium complex, the molecular mechanisms of their functions remain poorly understood. To dissect the mechanism for their regulatory roles during ciliogenesis, we performed an analysis to determine the proteins that localize in close proximity to the satellite protein CEP72, among which was the retinal degeneration gene product CCDC66. We identified CCDC66 as a microtubuleassociated protein that dynamically localizes to the centrosome, centriolar satellites and the primary cilium throughout the cell cycle. Like the BBSome component BBS4, CCDC66 distributes between satellites and the primary cilium during ciliogenesis. CCDC66 has extensive proximity interactions with centrosome and centriolar satellite proteins, and co-immunoprecipitation experiments revealed interactions between CCDC66, CEP290 and PCM1. Ciliogenesis, ciliary recruitment of BBS4 and centriolar satellite organization are impaired in cells depleted for CCDC66. Taken together, our findings identify CCDC66 as a targeting factor for centrosome and cilium proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

Section: Proximity Mapping Identifies New Centriolar Satellite Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The centriolar satellite protein CCDC66 interacts with CEP290 and functions in cilium formation and trafficking

Conkar

Culfa

Odabasi

et al. 2017

Journal of Cell Science

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Circular RNA CCDC66 facilitates abdominal aortic aneurysm through the overexpression of CCDC66

Yang

Wang

Meng

et al. 2020

Cell Biochemistry & Function

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Funding information The fifth group of bosom friends and talents plan of Hanyang District, Wuhan Abdominal aortic aneurysm (AAA) is fatal meanwhile unpredictable asymptomatic cardiovascular disease. Available data suggests the potential participation of circular RNAs (circRNAs) in AAA pathogenesis. But direct evidence is limited. The present study is to functionally and mechanically characterize circRNA CCDC66 (circCCDC66) in AAA. Previous work indicated the differentially expressed circCCDC66 in AAA. At molecular level, circCCDC66, miR-342-3p and CCDC66 transcript were measured through real-time quantitative polymerase chain reaction assay. Functionally, we examined the cellular behaviours of circCCDC66-depleted or CCDC66-depleted vascular smooth muscle cells (VSMCs) including proliferation and apoptosis. It elucidated that depletion of circCCDC66 induced proliferation facilitation and apoptosis reduction. Mechanically, we addressed the interplay among circCCDC66, miR-342-3p and CCDC66 transcript using RNA immunoprecipitation, RNA pull-down and luciferase reporter experiments. Through mechanical validation, we discovered the positive regulation of circCCDC66 on its host gene CCDC66. Loss of CCDC66 mimicked the effects of circCCDC66 silencing on VSMC growth. Moreover, it uncovered that circCCDC66 regulated CCDC66-dependent VSMC growth through sponging miR-342-3p. Rescue experiments aimed to address the functional role of regulatory network formed by circCCDC66, miR-342-3p and CCDC66 in VSMC growth and apoptosis. Suppressing miR-342-3p or overexpressing CCDC66 could reverse VSMC growth caused by circCCDC66 deficiency. Our study further emphasized and first unveiled the function of circCCDC66 in VSMC proliferation. CircCCDC66 upregulated its host gene through its role of miR-342-3p sponge, and hinted a novel molecular mechanism in AAA. Significance of the study: It was firstly displayed in our study that depletion of circCCDC66 induced proliferation augmentation and apoptosis reduction of vascular smooth muscle cells (VSMCs). Meanwhile, circCCDC66/miR-342-3p/CCDC66 axis was proved can play the function of modulating the cell proliferation and apoptosis of VSMCs, which provided us a novel molecular mechanism in AAA.

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Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

2011

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Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.

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Ccdc66 null mutation causes retinal degeneration and dysfunction

Cited by 38 publications

References 25 publications

The centriolar satellite protein CCDC66 interacts with CEP290 and functions in cilium formation and trafficking

The centriolar satellite protein CCDC66 interacts with CEP290 and functions in cilium formation and trafficking

Circular RNA CCDC66 facilitates abdominal aortic aneurysm through the overexpression of CCDC66

Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

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