Mutations inCCDC39andCCDC40are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms

Antony, Dinu; Becker-Heck, Anita; Zariwala, Maimoona A.; Schmidts, Miriam; Onoufriadis, Alexandros; Forouhan, Mitra; Wilson, Robert; Taylor-Cox, Theresa; Dewar, A.; Jackson, Claire; Goggin, Patricia; Loges, Niki T.; Olbrich, Heike; Jaspers, Martine; Jorissen, Mark; Leigh, Margaret W.; Wolf, Whitney E.; Daniels, M. Leigh Anne; Noone, Peadar G.; Ferkol, Thomas; Sagel, Scott D.; Rosenfeld, Margaret; Rutman, Andrew; Dixit, Abhijit; O’Callaghan, Christopher; Lucas, Jane S.; Hogg, Claire; Scambler, Peter J.; Emes, Richard D.; UKK,; Chung, Eddie M.K.; Shoemark, Amelia; Knowles, Michael R.; Omran, Heymut; Mitchison, Hannah M.

doi:10.1002/humu.22261

Cited by 178 publications

(155 citation statements)

References 59 publications

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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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248

289

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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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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

Self Cite

248

289

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show abstract

“…6 Ciliary motility was analysed by video microscopy from transnasal brush biopsies. High-speed (500 frames per second) video sequences of the cilia were captured using a MotionPro X4 camera (Lake Image Systems, Tring, UK) on an inverted Nikon Diaphot microscope (Nikon Instruments Europe, Amsterdam, Netherlands).…”

Section: Transmission Electron Microscopy and Video Microscopymentioning

confidence: 99%

Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population

et al. 2014

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We present a study of five children from three unrelated Irish Traveller families presenting with primary ciliary dyskinesia (PCD). As previously characterized disorders in the Irish Traveller population are caused by common homozygous mutations, we hypothesised that all three PCD families shared the same recessive mutation. However, exome sequencing showed that there was no pathogenic homozygous mutation common to all families. This finding was supported by histology, which showed that each family has a different type of ciliary defect; transposition defect (family A), nude epithelium (family B) and absence of inner and outer dynein arms (family C). Therefore, each family was analysed independently using homozygosity mapping and exome sequencing. The affected siblings in family A share a novel 1 bp duplication in RSPH4A (NM_001161664.1:c.166dup; p.Arg56Profs*11), a radial-spoke head protein involved in ciliary movement. In family B, we identified three candidate genes (CCNO, KCNN3 and CDKN1C), with a 5-bp duplication in CCNO (NM_021147.3:c.258_262dup; p.Gln88Argfs*8) being the most likely cause of ciliary aplasia. This is the first study to implicate CCNO, a DNA repair gene reported to be involved in multiciliogenesis, in PCD. In family C, we identified a B3.5-kb deletion in DYX1C1, a neuronal migration gene previously associated with PCD. This is the first report of a disorder in the relatively small Irish Traveller population to be caused by 41 disease gene. Our study identified at least three different PCD genes in the Irish Traveller population, highlighting that one cannot always assume genetic homogeneity, even in small consanguineous populations.

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“…All have previously been described to be associated with ciliary dyskinesia in either mice or humans, and in some cases both. 16,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] We find it of significance, therefore, that a large proportion of affected genes are associated with not only isomerism, but also with ciliary dyskinesia. Previous studies have shown that over 40% of patients with isomerism also have ciliary dyskinesia.…”

Section: Discussionmentioning

confidence: 64%

Genetic Disturbances in Patients with Bodily Isomerism from a Single Center: Clinical Implications of Affected Genes and Potential Impact of Ciliary Dyskinesia

Loomba

Frommelt

Anderson³

2016

Cardiogenetics

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So-called heterotaxy or isomerism is characterized by abnormal lateralization and malformations of the bodily organs. The mechanism is unclear, although there is growing evidence that ciliary dyskinesia is involved. We reviewed genetic findings from patients with isomerism to determine if affected genes were known to be associated with isomerism and ciliary dyskinesia and determine associations between genotype and clinical findings. We identified patients with isomerism cared for over a 16-year period. Characteristics were compared between those with and without identified mutations. A total of 83 patients with isomerism were identified. Of those who had genotyping, 14/27 had mutations identified, most frequently involving the CFC1 and NODAL genes. Specific mutations were associated with clinical findings, with NODAL mutations often portending need for increased clinical support. Genes associated with isomerism and/or ciliary dyskinesia were identified in the cohort. Specific gene mutations may help predict clinical course.

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Mutations inCCDC39andCCDC40are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms

Cited by 178 publications

References 59 publications

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

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

Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population

Genetic Disturbances in Patients with Bodily Isomerism from a Single Center: Clinical Implications of Affected Genes and Potential Impact of Ciliary Dyskinesia

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