The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation

Becker-Heck, Anita; Zohn, Irene E.; Okabe, Noriko; Pollock, Andrew; Lenhart, Kari Baker; Sullivan-Brown, Jessica; McSheene, Jason C.; Loges, Niki T.; Olbrich, Heike; Häeffner, Karsten; Fliegauf, Manfred; Horvath, Judith; Reinhardt, Richard; Nielsen, Kim G.; Marthin, June K; Baktai, G; Anderson, Kathryn V.; Geisler, Robert; Niswander, Lee; Omran, Heymut; Burdine, Rebecca D.

doi:10.1038/ng.727

Cited by 294 publications

(273 citation statements)

References 27 publications

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“…Interestingly Immunofluorescent antibodies revealed the presence of the IDA component protein DNALI1 in all these patients. This is in contrast to combined ODA and IDA defects caused by KTU and LRRC50 mutations as well as in respiratory cilia characterized by combined dynein regulatory complex (DRC)/IDA defects caused by CCDC39 and CCDC40 mutations, where DNALI1 is absent respectively [15][16][17][18]. This immunofluorescence finding confirms that at least a subset of IDAs can be assembled in these cases and excludes a complete IDA absence explaining difficulties at TEM.…”

Section: Discussionsupporting

confidence: 52%

Inner Dynein Arm Defects in Primary Ciliary Dyskinesia

Shoemark¹

2013

J Genet Syndr Gene Ther

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Primary ciliary dyskinesia (PCD) is a genetic condition in which there is a defect in cilia motility. This can be caused by the absence of the inner dynein arm motor (IDA). The IDA can be difficult to observe by electron microscopy and has been shown to transiently disappear, making accurate diagnosis difficult.This study reviewed cases of PCD due to an IDA defect on the Royal Brompton Hospital database in order to confirm or retract the diagnosis. This was achieved using current methods of diagnosis (nasal nitric oxide, light and electron microscopy) and new techniques to improve visualisation of the IDA such as immunofluorescence analysis and 3D electron tomography.

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Section: Discussionsupporting

confidence: 52%

Inner Dynein Arm Defects in Primary Ciliary Dyskinesia

Shoemark¹

2013

J Genet Syndr Gene Ther

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“…These organelles are present on the apical surface of most vertebrate cells and are involved in sensory, signalling and mechanical processes (Bisgrove and Yost, 2006;Ishikawa and Marshall, 2011). Every cell of the zebrafish OV epithelium is monociliated (Riley et al, 1997), and many genes involved in ciliogenesis, intraflagellar transport, ciliary movement, stability and function are expressed in the OV (Tsujikawa and Malicki, 2004;Bisgrove et al, 2005;Omori and Malicki, 2006;Pathak et al, 2007;Omori et al, 2008;SullivanBrown et al, 2008;van Rooijen et al, 2008;Yu et al, 2008;Colantonio et al, 2009;Wilkinson et al, 2009;Gao et al, 2010;Glazer et al, 2010;Kang et al, 2010;May-Simera et al, 2010;Becker-Heck et al, 2011;Clément et al, 2011;Pathak et al, 2011;Ravanelli and Klingensmith, 2011;Rothschild et al, 2011;Yu et al, 2011). Sensory hair cells in the ear each bear a specialised cilium known as the kinocilium.…”

Section: Introductionmentioning

confidence: 99%

The role of hair cells, cilia and ciliary motility in otolith formation in the zebrafish otic vesicle

et al. 2012

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SUMMARYOtoliths are biomineralised structures required for the sensation of gravity, linear acceleration and sound in the zebrafish ear. Otolith precursor particles, initially distributed throughout the otic vesicle lumen, become tethered to the tips of hair cell kinocilia (tether cilia) at the otic vesicle poles, forming two otoliths. We have used high-speed video microscopy to investigate the role of cilia and ciliary motility in otolith formation. In wild-type ears, groups of motile cilia are present at the otic vesicle poles, surrounding the immotile tether cilia. A few motile cilia are also found on the medial wall, but most cilia (92-98%) in the otic vesicle are immotile. In mutants with defective cilia (iguana) or ciliary motility (lrrc50), otoliths are frequently ectopic, untethered or fused. Nevertheless, neither cilia nor ciliary motility are absolutely required for otolith tethering: a mutant that lacks cilia completely (MZovl) is still capable of tethering otoliths at the otic vesicle poles. In embryos with attenuated Notch signalling [mindbomb mutant or Su(H) morphant], supernumerary hair cells develop and otolith precursor particles bind to the tips of all kinocilia, or bind directly to the hair cells' apical surface if cilia are absent [MZovl injected with a Su(H)1+2 morpholino]. However, if the first hair cells are missing (atoh1b morphant), otolith formation is severely disrupted and delayed. Our data support a model in which hair cells produce an otolith precursor-binding factor, normally localised to tether cell kinocilia. We also show that embryonic movement plays a minor role in the formation of normal otoliths.

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“…While tremendous progress has been made in recent years in unveiling the molecular mechanisms of the disease [2,3,[8][9][10][11][12][13][14][15][16][17][18][19], PCD management is still hampered by a lack of fundamental data on epidemiology, clinical presentation, disease course and effects of different treatment strategies [4][5][6]. Patient registries are well-known tools to assemble sufficient numbers of individuals with a rare disease to assess and monitor patient data in a standardised and longitudinal way, and to recruit candidates for clinical research studies [20,21].…”

Section: Introductionmentioning

confidence: 99%

An international registry for primary ciliary dyskinesia

et al. 2015

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Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder leading to chronic upper and lower airway disease. Fundamental data on epidemiology, clinical presentation, course and treatment strategies are lacking in PCD. We have established an international PCD registry to realise an unmet need for an international platform to systematically collect data on incidence, clinical presentation, treatment and disease course.The registry was launched in January 2014. We used internet technology to ensure easy online access using a web browser under www.pcdregistry.eu. Data from 201 patients have been collected so far. The database is comprised of a basic data form including demographic and diagnostic information, and visit forms designed to monitor the disease course.To establish a definite PCD diagnosis, we used strict diagnostic criteria, which required two to three diagnostic methods in addition to classical clinical symptoms. Preliminary analysis of lung function data demonstrated a mean annual decline of percentage predicted forced expiratory volume in 1 s of 0.59% (95% CI 0.98-0.22).Here, we present the development of an international PCD registry as a new promising tool to advance the understanding of this rare disorder, to recruit candidates for research studies and ultimately to improve PCD care. @ERSpublications A registry to systematically collect data on clinical presentation, disease course and treatment of PCD http://ow.ly/TtGAR

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The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation

Cited by 294 publications

References 27 publications

Inner Dynein Arm Defects in Primary Ciliary Dyskinesia

Inner Dynein Arm Defects in Primary Ciliary Dyskinesia

The role of hair cells, cilia and ciliary motility in otolith formation in the zebrafish otic vesicle

An international registry for primary ciliary dyskinesia

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