Deletions and Point Mutations of LRRC50 Cause Primary Ciliary Dyskinesia Due to Dynein Arm Defects

Loges, Niki T.; Olbrich, Heike; Becker-Heck, Anita; Häffner, Karsten; Heer, Angelina; Reinhard, Christina; Schmidts, Miriam; Kispert, Andreas; Zariwala, Maimoona A.; Leigh, Margaret W.; Knowles, Michael R.; Zentgraf, Hanswalter; Seithe, Horst; Nürnberg, Gudrun; Nürnberg, Peter; Reinhardt, Richard; Omran, Heymut

doi:10.1016/j.ajhg.2009.10.018

Cited by 205 publications

(169 citation statements)

References 19 publications

(29 reference statements)

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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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“…The identification of genes regulating cilia formation and function is the key first step towards understanding the biology of cilia and ciliopathies. Despite the fact that PCD ranks among the most prevalent of ciliopathies, causative mutations in a limited number of genes have been discovered, mainly in those encoding axonemal dynein subunits (Bartoloni et al, 2002;Loges et al, 2008;Mazor et al, 2011;Olbrich et al, 2002;Pennarun et al, 1999) and dynein motor assembly proteins (Kott et al, 2012;Loges et al, 2009;Mitchison et al, 2012;Omran et al, 2008). These mutations account for fewer than two-thirds of the total cases of PCD (Zariwala et al, 2011), indicating that a large number of motile cilia genes whose mutations cause PCD have yet to be identified.…”

Section: Introductionmentioning

confidence: 99%

Systematic discovery of novel ciliary genes through functional genomics in the zebrafish

Choksi

Babu

Lau

et al. 2014

Journal of Cell Science

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Cilia are microtubule-based hair-like organelles that play many important roles in development and physiology, and are implicated in a rapidly expanding spectrum of human diseases, collectively termed ciliopathies. Primary ciliary dyskinesia (PCD), one of the most prevalent of ciliopathies, arises from abnormalities in the differentiation or motility of the motile cilia. Despite their biomedical importance, a methodical functional screen for ciliary genes has not been carried out in any vertebrate at the organismal level. We sought to systematically discover novel motile cilia genes by identifying the genes induced by Foxj1, a winged-helix transcription factor that has an evolutionarily conserved role as the master regulator of motile cilia biogenesis. Unexpectedly, we find that the majority of the Foxj1-induced genes have not been associated with cilia before. To characterize these novel putative ciliary genes, we subjected 50 randomly selected candidates to a systematic functional phenotypic screen in zebrafish embryos. Remarkably, we find that over 60% are required for ciliary differentiation or function, whereas 30% of the proteins encoded by these genes localize to motile cilia. We also show that these genes regulate the proper differentiation and beating of motile cilia. This collection of Foxj1-induced genes will be invaluable for furthering our understanding of ciliary biology, and in the identification of new mutations underlying ciliary disorders in humans.

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“…For nNO validation studies at six (non-UNC) sites, PCD was confirmed by PCD-specific ciliary EM defects and, by the presence of biallelic mutations in PCD genes (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Informed consent was obtained at the University of North Carolina at Chapel Hill and collaborating institutions under the auspices of Committees on the Protection of the Rights of Human Subjects.…”

Section: Original Researchmentioning

confidence: 99%

Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia

Leigh¹,

Hazucha²,

Chawla³

et al. 2013

Annals ATS

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Rationale: Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized.Objectives: To use a standard protocol for measuring nNO to establish a diseasespecific cutoff value at one site, and then validate at six other sites.Methods: At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD. Measurements and Main Results:At the lead site, nNO values in PCD (mean 6 standard deviation, 20.7 6 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 6 118.8; 125.5-867.0 nl/min), asthma (267.8 6 103.2; 125.0-589.7 nl/min), or chronic obstructive pulmonary disease (223.7 6 87.1; 109.7-449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 6 73.5; 15.6-386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, .0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD.Conclusions: Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.

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Deletions and Point Mutations of LRRC50 Cause Primary Ciliary Dyskinesia Due to Dynein Arm Defects

Cited by 205 publications

References 19 publications

Inner Dynein Arm Defects in Primary Ciliary Dyskinesia

Inner Dynein Arm Defects in Primary Ciliary Dyskinesia

Systematic discovery of novel ciliary genes through functional genomics in the zebrafish

Standardizing Nasal Nitric Oxide Measurement as a Test for Primary Ciliary Dyskinesia

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