OFD1, as a Ciliary Protein, Exhibits Neuroprotective Function in Photoreceptor Degeneration Models

Wang, Juan; Chen, Xin; Wang, Fang; Zhang, Jieping; Li, Zongyi; Xu, Jingying; Gao, Furong; Jin, Can; Tian, Haibin; Zhang, Jingfa; Li, Weiye; Lü, Lixia; Xu, Guo‐Tong

doi:10.1371/journal.pone.0155860

Cited by 14 publications

(9 citation statements)

References 50 publications

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“…These antiviral genes are also observed in infections with other respiratory viruses such as RV and RSV ( Huong et al, 2018 ; Tan et al, 2018 ). This is accompanied by reduction in ciliogenesis markers, MCIDAS and CCNO , and increase in OFD1 , a gene that encodes a centrosomal protein inhibiting ciliogenesis ( Wang et al, 2016 ). In addition, cilia dynein markers DNAH5 and DNAAF5 were found to be reduced, whereas TUBB6 was elevated following IFV H3N2 infection.…”

Section: Resultsmentioning

confidence: 99%

Host Antiviral Response Suppresses Ciliogenesis and Motile Ciliary Functions in the Nasal Epithelium

Chen

Tan

Liu

et al. 2020

Front. Cell Dev. Biol.

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BackgroundRespiratory viral infections are one of the main drivers of development and exacerbation for chronic airway inflammatory diseases. Increased viral susceptibility and impaired mucociliary clearance are often associated with chronic airway inflammatory diseases and served as risk factors of exacerbations. However, the links between viral susceptibility, viral clearance, and impaired mucociliary functions are unclear. Therefore, the objective of this study is to provide the insights into the effects of improper clearance of respiratory viruses from the epithelium following infection, and their resulting persistent activation of antiviral response, on mucociliary functions.MethodsIn order to investigate the effects of persistent antiviral responses triggered by viral components from improper clearance on cilia formation and function, we established an in vitro air–liquid interface (ALI) culture of human nasal epithelial cells (hNECs) and used Poly(I:C) as a surrogate of viral components to simulate their effects toward re-epithelization and mucociliary functions of the nasal epithelium following damages from a viral infection.ResultsThrough previous and current viral infection expression data, we found that respiratory viral infection of hNECs downregulated motile cilia gene expression. We then further tested the effects of antiviral response activation on the differentiation of hNECs using Poly(I:C) stimulation on differentiating human nasal epithelial stem/progenitor cells (hNESPCs). Using this model, we observed reduced ciliated cell differentiation compared to goblet cells, reduced protein and mRNA in ciliogenesis-associated markers, and increased mis-assembly and mis-localization of ciliary protein DNAH5 following treatment with 25 μg/ml Poly(I:C) in differentiating hNECs. Additionally, the cilia length and ciliary beat frequency (CBF) were also decreased, which suggest impairment of ciliary function as well.ConclusionOur results suggest that the impairments of ciliogenesis and ciliary function in hNECs may be triggered by specific expression of host antiviral response genes during re-epithelization of the nasal epithelium following viral infection. This event may in turn drive the development and exacerbation of chronic airway inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Host Antiviral Response Suppresses Ciliogenesis and Motile Ciliary Functions in the Nasal Epithelium

Chen

Tan

Liu

et al. 2020

Front. Cell Dev. Biol.

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“…Endogenous CEP250 in mouse retinal cryosections (P60) was mostly detected in the outer photoreceptor segment (Fig 4A), supporting its localization in the photoreceptor axoneme (Fig 4B). Other centrosomal proteins that cause IRD, such as OFD1, share a similar localization pattern in the retina[43]. Furthermore, localization of the wild-type and A609V CEP250 proteins was studied in transfected human ARPE19 cells where cilia formation was promoted after serum-starvation.…”

Section: Resultsmentioning

confidence: 99%

Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing

et al. 2016

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BackgroundNGS-based genetic diagnosis has completely revolutionized the human genetics field. In this study, we have aimed to identify new genes and mutations by Whole Exome Sequencing (WES) responsible for inherited retinal dystrophies (IRD).MethodsA cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. Initial prioritization analysis included around 300 IRD-associated genes. In non-diagnosed families a search for pathogenic mutations in novel genes was undertaken.ResultsGenetic diagnosis was attained in 18 families. Moreover, a plausible candidate is proposed for 10 more cases. Two thirds of the mutations were novel, including 4 chromosomal rearrangements, which expand the IRD allelic heterogeneity and highlight the contribution of private mutations. Our results prompted clinical re-evaluation of some patients resulting in assignment to a syndromic instead of non-syndromic IRD. Notably, WES unveiled four new candidates for non-syndromic IRD: SEMA6B, CEP78, CEP250, SCLT1, the two latter previously associated to syndromic disorders. We provide functional data supporting that missense mutations in CEP250 alter cilia formation.ConclusionThe diagnostic efficiency of WES, and strictly following the ACMG/AMP criteria is 55% in reported causative genes or functionally supported new candidates, plus 30% families in which likely pathogenic or VGUS/VUS variants were identified in plausible candidates. Our results highlight the clinical utility of WES for molecular diagnosis of IRD, provide a wider spectrum of mutations and concomitant genetic variants, and challenge our view on syndromic vs non-syndromic, and causative vs modifier genes.

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“…C-Nap1 has been reported to be expressed in photoreceptor cilia and is also known to interact with other ciliary proteins including rootletin and NEK2 (13). Other centrosomal proteins that cause inherited retinal diseases, such as OFD1, share a similar localization pattern in the retina (14). Functional studies of ARPE19 cells in culture also support an involvement of CEP250 in retinal ciliogenesis (15).…”

Section: Introductionmentioning

confidence: 88%

CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family

Kubota

Gocho

Kikuchi

et al. 2018

Ophthalmic Genetics

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The variants of CEP250 are both null variants and according to American College of Medical Genetics and Genomics (ACMG) standards and guideline, these variants are classified into the very strong category (PVS1). The criteria for both alleles will be pathogenic. Our data indicate that mutations of CEP250 can cause mild CRD and SNHL in Japanese patients. Because the ophthalmological phenotypes were very mild, high-resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease.

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OFD1, as a Ciliary Protein, Exhibits Neuroprotective Function in Photoreceptor Degeneration Models

Cited by 14 publications

References 50 publications

Host Antiviral Response Suppresses Ciliogenesis and Motile Ciliary Functions in the Nasal Epithelium

Host Antiviral Response Suppresses Ciliogenesis and Motile Ciliary Functions in the Nasal Epithelium

Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing

CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family

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