Systematic Analysis of<i>CCNO</i>Variants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis

Amirav, Israel; Wallmeier, Julia; Loges, Niki T.; Menchen, Tabea; Pennekamp, Petra; Mussaffi, Huda; Abitbul, Revital; Avital, Avraham; Bentur, Lea; Dougherty, Gerard W.; Elias, Nael; Lavie, Moran; Olbrich, Heike; Werner, Claudius; Kintner, Chris; Omran, Heymut

doi:10.1002/humu.22957

Cited by 82 publications

(90 citation statements)

References 21 publications

(65 reference statements)

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“…in DNAI1 [106] and DNAH5 [69]) and mutational hot spots (e.g. CCNO [107]) have been reported. The ranking of the effect of the mutations should follow international recommendations [108]: benign (class 1), likely benign (class 2), unknown significance (class 3), likely pathogenic (class 4), pathogenic (class 5).…”

Section: Resultsmentioning

confidence: 99%

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

et al. 2016

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The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no ‘gold standard’ reference test. Hence, a task force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in the light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on: clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of PCD; also to provide advice when the diagnosis is not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for PCD.

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Section: Resultsmentioning

confidence: 99%

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

et al. 2016

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“…Downstream from the MCIDAS/E2F complex also lies CCNO ( Fig. 1) (Stubbs et al 2012;Ma et al 2014;Wallmeier et al 2014), a cyclin-like protein first shown to be involved in oocyte meiosis resumption and apoptosis (Roig et al 2009;Ma et al 2013), and then shown to be expressed in MCC progenitors in the Xenopus skin and in the mouse brain, airways, and oviducts (Stubbs et al 2012;Funk et al 2015;Amirav et al 2016). Although its partners and molecular function remain to be determined, CCNO mutations or depletion lead to defects comparable to the C-MYB phenotype: defects in BB amplification, docking, and ciliogenesis Funk et al 2015).…”

Section: Downstream Effectors Of the MCC Differentiation Programmentioning

confidence: 99%

“…Although its partners and molecular function remain to be determined, CCNO mutations or depletion lead to defects comparable to the C-MYB phenotype: defects in BB amplification, docking, and ciliogenesis Funk et al 2015). In humans, mutations in CCNO have been identified as a cause of RGMC and associated with hydrocephalus and female infertility Amirav et al 2016). Interestingly, human mcidas, ccno, and miR449 host gene cdc20b are physically colocalized in a genomic region of chromosome 5 and are syntenic with those of Xenopus and mouse (Marcet et al 2011;Stubbs et al 2012;Wallmeier et al 2014).…”

Section: Downstream Effectors Of the MCC Differentiation Programmentioning

confidence: 99%

Multiciliated Cells in Animals

Meunier¹,

Azimzadeh²

2016

Cold Spring Harb Perspect Biol

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Many animal cells assemble single cilia involved in motile and/or sensory functions. In contrast, multiciliated cells (MCCs) assemble up to 300 motile cilia that beat in a coordinate fashion to generate a directional fluid flow. In the human airways, the brain, and the oviduct, MCCs allow mucus clearance, cerebrospinal fluid circulation, and egg transportation, respectively. Impairment of MCC function leads to chronic respiratory infections and increased risks of hydrocephalus and female infertility. MCC differentiation during development or repair involves the activation of a regulatory cascade triggered by the inhibition of Notch activity in MCC progenitors. The downstream events include the simultaneous assembly of a large number of basal bodies (BBs)-from which cilia are nucleated-in the cytoplasm of the differentiating MCCs, their migration and docking at the plasma membrane associated to an important remodeling of the actin cytoskeleton, and the assembly and polarization of motile cilia. The direction of ciliary beating is coordinated both within cells and at the tissue level by a combination of planar polarity cues affecting BB position and hydrodynamic forces that are both generated and sensed by the cilia. Herein, we review the mechanisms controlling the specification and differentiation of MCCs and BB assembly and organization at the apical surface, as well as ciliary assembly and coordination in MCCs.

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“…Nasal nitric oxide values are low in patients with CCNO or MCIDAS mutations. 35–37 High speed videomicroscopy analysis is normally unfeasible in these patients, as locating the few residual cilia per epithelial cell proves difficult, and reviewers often mistakenly conclude that the lack of cilia stems from a secondary process.…”

Section: Specific Forms Of Pcd With Normal Tem Ultrastructurementioning

confidence: 99%

“…11 However in one Israeli cohort with mucociliary clearance disorders, 11 out of 171 families (6.5%) had biallelic mutations in CCNO (n=10) or MICDAS (n=1) causing their disease. 37 An increased prevalence for PCD in the Irish Traveler population exists with the CCNO gene. 38 Mutations in CCNO and MCIDAS are detected on commercial PCD genetic panels.…”

Section: Specific Forms Of Pcd With Normal Tem Ultrastructurementioning

confidence: 99%

Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in the era of molecular medicine: Genetic defects with normal and non-diagnostic ciliary ultrastructure

Shapiro

Leigh

2017

Ultrastructural Pathology

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Primary Ciliary Dyskinesia (PCD) is a genetic disorder causing chronic oto-sino-pulmonary disease. No single diagnostic test will detect all PCD cases. Transmission electron microscopy (TEM) of respiratory cilia was previously considered the gold standard diagnostic test for PCD, but 30% of all PCD cases have either normal ciliary ultrastructure or subtle changes which are non-diagnostic. These cases are identified through alternate diagnostic tests, including nasal nitric oxide measurement, high speed videomicroscopy analysis, immunofluorescent staining of axonemal proteins, and/or mutation analysis of various PCD causing genes. Autosomal recessive mutations in DNAH11 and HYDIN produce normal TEM ciliary ultrastructure, while mutations in genes encoding for radial spoke head proteins result in some cross-sections with non-diagnostic alterations in the central apparatus interspersed with normal ciliary cross-sections. Mutations in nexin link and dynein regulatory complex genes lead to a collection of different ciliary ultrastructures; mutations in CCDC65, CCDC164, and GAS8 produce normal ciliary ultrastructure, while mutations in CCDC39 and CCDC40 cause absent inner dynein arms and microtubule disorganization in some ciliary cross-sections. Mutations in CCNO and MCIDAS cause near complete absence of respiratory cilia due to defects in generation of multiple cellular basal bodies; however, the scant cilia generated may have normal ultrastructure. Lastly, a syndromic form of PCD with retinal degeneration results in normal ciliary ultrastructure through mutations in the RPGR gene. Clinicians must be aware of these genetic causes of PCD resulting in non-diagnostic TEM ciliary ultrastructure and refrain from using TEM of respiratory cilia as a test to rule out PCD.

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Systematic Analysis ofCCNOVariants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis

Cited by 82 publications

References 21 publications

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

Multiciliated Cells in Animals

Value of transmission electron microscopy for primary ciliary dyskinesia diagnosis in the era of molecular medicine: Genetic defects with normal and non-diagnostic ciliary ultrastructure

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