Delineation of<i>CCDC39/CCDC40</i>mutation spectrum and associated phenotypes in primary ciliary dyskinesia

Blanchon, Sylvain; Legendre, M.; Copin, Bruno; Duquesnoy, Philippe; Montantin, Guy; Kott, Esther; Dastot, Florence; Jeanson, Ludovic; Cachanado, Marine; Rousseau, Alexandra; Papon, Jean‐François; Beydon, N; Brouard, J.; Crestani, Bruno; Deschildre, A.; Désir, Julie; Dollfus, Hélène; Leheup, Bruno; Tamalet, Aline; Thumerelle, C.; Vojtek, Anne-Marie; Escalier, Denise; Coste, A.; Blic, J. de; Clément, Annick; Escudier, Estelle; Amselem, Serge

doi:10.1136/jmedgenet-2012-100867

Cited by 85 publications

(51 citation statements)

References 18 publications

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“…Recently, we, and others, found that recessive mutations in CCDC39 and CCDC40 cause PCD with severe ultrastructural defects such as marked tubular disorganization with displacement of peripheral outer doublets as well as the central pair apparatus and associated IDA defects 10,11,29 . Defective N-DRC and inner dynein arm assembly in CCDC39 and CCDC40 mutant cilia is characterized by absence of the DRC component GAS11 (DRC4) and the inner dynein arm light chain DNALI1 (orthologous to Chlamydomonas light chain p28) from the ciliary axonemes.…”

Section: Resultsmentioning

confidence: 94%

The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans

et al. 2013

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Summary Primary ciliary dyskinesia (PCD) is characterized by dysfunction in respiratory and reproductive cilia/flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the Nexin-Dynein Regulatory Complex (N-DRC), an axonemal structure critical for regulation of the dynein motors, and demonstrate that DRC1/CCDC164 mutations are involved in the pathogenesis of PCD. Loss-of-function DRC1/CCDC164 mutations result in severe defects in assembly of the N-DRC structure and defective ciliary movement in Chlamydomonas and humans. Our results highlight the role of N-DRC integrity for regulation of ciliary beating and provide the first direct evidence that drc mutations cause human disease.

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Section: Resultsmentioning

confidence: 94%

The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans

et al. 2013

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“…Mutational analysis of PCD patients identified a number of families with mutations in CCDC39 and CCDC40 (6, 12, 20, 98). Immunofluorescence analysis of airway cilia samples from CCDC39 and 40 patients found a loss of GAS11, a component of the dynein regulatory complex (DRC), and DNALI1, a member of the IDA light chain family, from ciliary axonemes (12, 98).…”

Section: Human Ciliopathiesmentioning

confidence: 99%

Expanding Horizons: Ciliary Proteins Reach Beyond Cilia

Yuan

Sun

2013

Annu. Rev. Genet.

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Once obscure, the cilium has come into the spotlight during the past decade. It is now clear that aside from generating locomotion by motile cilia, both motile and immotile cilia serve as signaling platforms for the cell. Through both motility and sensory functions, cilia play critical roles in development, homeostasis, and disease. To date, the cilium proteome contains more than 1,000 different proteins, and human genetics is identifying new ciliopathy genes at an increasing pace. Although assigning a function to immotile cilia was a challenge not so long ago, the myriad of signaling pathways, proteins, and biological processes associated with the cilium have now created a new obstacle: how to distill all these interactions into specific themes and mechanisms that may explain how the organelle serves to maintain organism homeostasis. Here, we review the basics of cilia biology, novel functions associated with cilia, and recent advances in cilia genetics, and on the basis of this framework, we further discuss the meaning and significance of ciliary connections.

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“…Of note, subjects with DNAH11 (MIM 603339) mutations present with a clinical phenotype consistent with PCD, but with no ultrastructural defects detectable using standard transmission EM [15]. Mutations in other genes such as CCDC39 (MIM 613798) and CCDC40 (MIM 613799) produce inconsistent ultrastructural abnormalities characterized by disordered microtubules in only some respiratory cells [14], [19], [20], which underscores the limitations of EM as a diagnostic test for PCD [15].…”

Section: Introductionmentioning

confidence: 99%

CCDC65 Mutation Causes Primary Ciliary Dyskinesia with Normal Ultrastructure and Hyperkinetic Cilia

et al. 2013

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BackgroundPrimary ciliary dyskinesia (PCD) is a genetic disorder characterized by impaired ciliary function, leading to chronic sinopulmonary disease. The genetic causes of PCD are still evolving, while the diagnosis is often dependent on finding a ciliary ultrastructural abnormality and immotile cilia. Here we report a novel gene associated with PCD but without ciliary ultrastructural abnormalities evident by transmission electron microscopy, but with dyskinetic cilia beating.MethodsGenetic linkage analysis was performed in a family with a PCD subject. Gene expression was studied in Chlamydomonas reinhardtii and human airway epithelial cells, using RNA assays and immunostaining. The phenotypic effects of candidate gene mutations were determined in primary culture human tracheobronchial epithelial cells transduced with gene targeted shRNA sequences. Video-microscopy was used to evaluate cilia motion.ResultsA single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD. CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband. CCDC65 expression was up-regulated during ciliogenesis in cultured airway epithelial cells, as was DRC2 in C. reinhardtii following deflagellation. Nasal epithelial cells from the affected individual and CCDC65-specific shRNA transduced normal airway epithelial cells had stiff and dyskinetic cilia beating patterns compared to control cells. Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells.ConclusionMutation in CCDC65, a nexin-dynein regulatory complex member, resulted in a frameshift mutation and PCD. The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis.

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Delineation ofCCDC39/CCDC40mutation spectrum and associated phenotypes in primary ciliary dyskinesia

Cited by 85 publications

References 18 publications

The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans

The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans

Expanding Horizons: Ciliary Proteins Reach Beyond Cilia

CCDC65 Mutation Causes Primary Ciliary Dyskinesia with Normal Ultrastructure and Hyperkinetic Cilia

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