Genomes and Genes
Summary: An autosomal recessive disorder characterized by a triad of DEXTROCARDIA; INFERTILITY; and SINUSITIS. The syndrome is caused by mutations of DYNEIN genes encoding motility proteins which are components of sperm tails, and CILIA in the respiratory and the reproductive tracts.
- Stannard W, Rutman A, Wallis C, O Callaghan C. Central microtubular agenesis causing primary ciliary dyskinesia. Am J Respir Crit Care Med. 2004;169:634-7 pubmed..In addition, this defect, together with the transposition defect, may help explain the mechanism of the circular beat pattern and also the absence of situs inversus in these patients. ..
- Failly M, Saitta A, Munoz A, Falconnet E, Rossier C, Santamaria F, et al. DNAI1 mutations explain only 2% of primary ciliary dykinesia. Respiration. 2008;76:198-204 pubmed publisher..We conclude that DNAI1 gene mutation is not a common cause of PCD, and that major or several additional disease gene(s) still remain to be identified before a sensitive molecular diagnostic test can be developed for PCD. ..
- Failly M, Bartoloni L, Letourneau A, Munoz A, Falconnet E, Rossier C, et al. Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia. J Med Genet. 2009;46:281-6 pubmed publisher..Overall, mutations on both alleles of DNAH5 were identified in 15% of our clinically heterogeneous cohort of patients. Although genetic alterations remain to be identified in most patients, DNAH5 is to date the main PCD gene. ..
- Horani A, Ferkol T, Shoseyov D, Wasserman M, Oren Y, Kerem B, et al. LRRC6 mutation causes primary ciliary dyskinesia with dynein arm defects. PLoS ONE. 2013;8:e59436 pubmed publisher..These findings suggest that LRRC6 plays a role in dynein arm assembly or trafficking and when mutated leads to primary ciliary dyskinesia with laterality defects. ..
- Loges N, Olbrich H, Becker Heck A, Haffner K, Heer A, Reinhard C, et al. Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am J Hum Genet. 2009;85:883-9 pubmed publisher..On the basis of these findings, we assume that LRRC50 plays a role in assembly of distinct dynein-arm complexes. ..
- Armengot M, Milara J, Mata M, Carda C, Cortijo J. Cilia motility and structure in primary and secondary ciliary dyskinesia. Am J Rhinol Allergy. 2010;24:175-80 pubmed publisher..Video analysis is probably more useful than the study of mucociliary transport and cilia ultrastructure in screening for PCD. The absence of dynein was correlated with ciliary immotility and was more common in KS patients. ..
- Antony D, Becker Heck A, Zariwala M, Schmidts M, Onoufriadis A, Forouhan M, et al. Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Hum Mutat. 2013;34:462-72 pubmed publisher..We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as "IDA and microtubular disorganisation defect," rather than "radial spoke defect." ..
- Serapinas D, Staikūniene J, Barkauskiene D, Jackute J, Sakalauskas R. An unusual regression of the symptoms of Kartagener syndrome. Arch Bronconeumol. 2013;49:28-30 pubmed publisher..The present case discusses the complex interrelationship between the genetic variation and a proper nonspecific management of Kartagener's syndrome. ..
- Marthin J, Nielsen K. Choice of nasal nitric oxide technique as first-line test for primary ciliary dyskinesia. Eur Respir J. 2011;37:559-65 pubmed publisher..nNO is a helpful first-line tool in real-life PCD work-up in all age groups if the sampling method is chosen according to age. nNO can be misleading in a few patients with true PCD. Further studies are strongly needed in young children. ..
- Mitchison H, Schmidts M, Loges N, Freshour J, Dritsoula A, Hirst R, et al. Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia. Nat Genet. 2012;44:381-9, S1-2 pubmed publisher..These results support the existence of a conserved, multistep pathway for the cytoplasmic formation of assembly competent ciliary dynein complexes...
- Olbrich H, Haffner K, Kispert A, Völkel A, Volz A, Sasmaz G, et al. Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat Genet. 2002;30:143-4 pubmed..Here we characterize the full-length 14-kb transcript of DNAH5. Sequence analysis in individuals with PCD with randomization of LR asymmetry identified mutations resulting in non-functional DNAH5 proteins. ..
- Blanchon S, Legendre M, Copin B, Duquesnoy P, Montantin G, Kott E, et al. Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. J Med Genet. 2012;49:410-6 pubmed publisher..CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other. ..
- Skrzypczak U, Rutkiewicz E, Pogorzelski A, Witt M, Zietkiewicz E. Carrier status for 3 most frequent CFTR mutations in Polish PCD/KS patients: lack of association with the primary ciliary dyskinesia phenotype. J Appl Genet. 2007;48:85-8 pubmedWe screened a large group of primary ciliary dyskinesia/Kartagener syndrome (PCD/KS) patients and their siblings (148 patients from 126 unrelated families) for the presence of the CFTR mutations that are most frequently found in the ..
- Hornef N, Olbrich H, Horvath J, Zariwala M, Fliegauf M, Loges N, et al. DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med. 2006;174:120-6 pubmed..DNAH5 is frequently mutated in patients with PCD exhibiting outer dynein arm defects and mutations cluster in five exons. ..
- McManus C. Eponymous but anonymous: who was Dr Siewert?. Lancet. 2004;363:662 pubmed
- el Zein L, Omran H, Bouvagnet P. Lateralization defects and ciliary dyskinesia: lessons from algae. Trends Genet. 2003;19:162-7 pubmed..In this article, we will discuss how information gained from studies on algae has aided research into these human diseases. These studies found a variety of functions that was previously unsuspected, renewing interest in cilia. ..
- Tarkar A, Loges N, Slagle C, Francis R, Dougherty G, Tamayo J, et al. DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet. 2013;45:995-1003 pubmed publisher..Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4)...
- Mazor M, Alkrinawi S, Chalifa Caspi V, Manor E, Sheffield V, Aviram M, et al. Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1. Am J Hum Genet. 2011;88:599-607 pubmed publisher..This study adds another important component to understanding the types of mutations that cause PCD and provides clinical information regarding a specific mutation in a gene not yet known to be associated with PCD. ..
- Zariwala M, Leigh M, Ceppa F, Kennedy M, Noone P, Carson J, et al. Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. Am J Respir Crit Care Med. 2006;174:858-66 pubmed..This information is useful for establishing a clinical molecular genetic test for PCD. ..
- Thomas B, Rutman A, O Callaghan C. Disrupted ciliated epithelium shows slower ciliary beat frequency and increased dyskinesia. Eur Respir J. 2009;34:401-4 pubmed publisher..Ideally, the assessment of ciliary beat pattern and frequency for PCD diagnosis should only be performed on undisrupted ciliated edges. ..
- Noone P, Leigh M, Sannuti A, Minnix S, Carson J, Hazucha M, et al. Primary ciliary dyskinesia: diagnostic and phenotypic features. Am J Respir Crit Care Med. 2004;169:459-67 pubmed..An increased awareness of the clinical presentation and diagnostic criteria for PCD will help lead to better diagnosis and care for this orphan disease. ..
- Pifferi M, Bush A, Pioggia G, Caramella D, Tartarisco G, Di Cicco M, et al. Evaluation of pulmonary disease using static lung volumes in primary ciliary dyskinesia. Thorax. 2012;67:993-9 pubmed publisher..Plethysmography better predicts HRCT abnormalities than spirometry. Whether it might be a useful test to define populations of patients with PCD who should or should not have HRCT scans requires further longitudinal studies. ..
- Olbrich H, Schmidts M, Werner C, Onoufriadis A, Loges N, Raidt J, et al. Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. Am J Hum Genet. 2012;91:672-84 pubmed publisher..Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus. ..
- Horie M, Arai H, Noguchi S, Suzuki M, Sakamoto Y, Oka T. [Kartagener syndrome with lung cancer and mediastinal tumor]. Nihon Kokyuki Gakkai Zasshi. 2010;48:375-8 pubmed..He died 1 year after the diagnosis of lung cancer was established. There have been 5 reported cases of Kartagener syndrome complicated with lung cancer, but to the best of our knowledge there have been no reports of Kartagener ..
- Kunimoto K, Yamazaki Y, Nishida T, Shinohara K, Ishikawa H, Hasegawa T, et al. Coordinated ciliary beating requires Odf2-mediated polarization of basal bodies via basal feet. Cell. 2012;148:189-200 pubmed publisher..The requirement for Odf2 in basal foot formation, therefore, reveals a crucial role of this structure in the polarized alignment of basal bodies and coordinated ciliary beating. ..
- Ibanez Tallon I, Gorokhova S, Heintz N. Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus. Hum Mol Genet. 2002;11:715-21 pubmed..Comparison of the mouse model and the human data suggests that the degree of ciliary dysfunction is causally related to the severity of human PCD, particularly the presence of hydrocephalus. ..
- Narang I, Ersu R, Wilson N, Bush A. Nitric oxide in chronic airway inflammation in children: diagnostic use and pathophysiological significance. Thorax. 2002;57:586-9 pubmed..eNO and nNO cannot be used diagnostically to distinguish between most respiratory diseases. However, nNO in particular is a quick and useful diagnostic marker which may be used to screen patients with a clinical suspicion of PCD. ..
- Papon J, Coste A, Roudot Thoraval F, Boucherat M, Roger G, Tamalet A, et al. A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia. Eur Respir J. 2010;35:1057-63 pubmed publisher..2%) or central complex (CC) (18.8%). Situs inversus was never observed in PCD patients with CC defect. Kartagener syndrome with normal ciliary ultrastructure was not an exceptional condition (10.2% of PCD)...
- Knowles M, Boucher R. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest. 2002;109:571-7 pubmed
- Knowles M, Daniels L, Davis S, Zariwala M, Leigh M. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med. 2013;188:913-22 pubmed publisher..The PCD Foundation is developing a network of clinical centers, which should improve diagnosis and management of PCD. ..
- McManus I, Stubbings G, Martin N. Stigmatization, physical illness and mental health in primary ciliary dyskinesia. J Health Psychol. 2006;11:467-82 pubmed..Neuroticism, extroversion, openness to experience, age, age at diagnosis and being female indirectly affected stigmatization via mental health. ..
- Guichard C, Harricane M, Lafitte J, Godard P, Zaegel M, Tack V, et al. Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome). Am J Hum Genet. 2001;68:1030-5 pubmedb>Kartagener syndrome (KS) is a trilogy of symptoms (nasal polyps, bronchiectasis, and situs inversus totalis) that is associated with ultrastructural anomalies of cilia of epithelial cells covering the upper and lower respiratory tracts ..
- Schwabe G, Hoffmann K, Loges N, Birker D, Rossier C, de Santi M, et al. Primary ciliary dyskinesia associated with normal axoneme ultrastructure is caused by DNAH11 mutations. Hum Mutat. 2008;29:289-98 pubmed..an inherited disorder characterized by perturbed or absent beating of motile cilia, which is referred to as Kartagener syndrome (KS) when associated with situs inversus...
- Yamashita S, Migita A, Hayashi K, Hirahara T, Kimura E, Maeda Y, et al. Amyotrophic lateral sclerosis in a patient with Kartagener syndrome. Amyotroph Lateral Scler. 2010;11:402-4 pubmed publisherWe present a case of a patient with clinically definite ALS, who had earlier suffered from Kartagener syndrome, which is characterized by the triad comprising chronic sinusitis, bronchiectasis, and situs inversus...
- Santamaria F, De Stefano S, Montella S, Barbarano F, Iacotucci P, Ciccarelli R, et al. Nasal nitric oxide assessment in primary ciliary dyskinesia using aspiration, exhalation, and humming. Med Sci Monit. 2008;14:CR80-85 pubmed..nNO is consistently low in PCD with good specificity and sensitivity whatever the method used for NO measurement. The extremely low levels of nNO during humming support the notion that NO is defective in the paranasal sinuses in PCD. ..
- Morillas H, Zariwala M, Knowles M. Genetic causes of bronchiectasis: primary ciliary dyskinesia. Respiration. 2007;74:252-63 pubmed
- Kott E, Legendre M, Copin B, Papon J, Dastot Le Moal F, Montantin G, et al. Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. Am J Hum Genet. 2013;93:561-70 pubmed publisher..RSPH1 mutations thus appear as a major etiology for this PCD phenotype, which in fact includes RS defects, thereby unveiling the importance of RSPH1 in the proper building of CCs and RSs in humans. ..
- Strippoli M, Frischer T, Barbato A, Snijders D, Maurer E, Lucas J, et al. Management of primary ciliary dyskinesia in European children: recommendations and clinical practice. Eur Respir J. 2012;39:1482-91 pubmed publisher..Our results also demonstrate the urgent need for research: to simplify PCD diagnosis, to understand the natural history and to test the effectiveness of interventions. ..
- Geremek M, Bruinenberg M, Zietkiewicz E, Pogorzelski A, Witt M, Wijmenga C. Gene expression studies in cells from primary ciliary dyskinesia patients identify 208 potential ciliary genes. Hum Genet. 2011;129:283-93 pubmed publisher..Our predictions are based directly on the human material and not on model organisms. This list of genes provides candidate genes for PCD and other ciliopathies. ..
- Ostrowski L, Yin W, Rogers T, Busalacchi K, Chua M, O Neal W, et al. Conditional deletion of dnaic1 in a murine model of primary ciliary dyskinesia causes chronic rhinosinusitis. Am J Respir Cell Mol Biol. 2010;43:55-63 pubmed publisher..This model will be useful for the study of the pathogenesis and treatment of PCD. ..
- Kennedy M, Omran H, Leigh M, Dell S, Morgan L, Molina P, et al. Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation. 2007;115:2814-21 pubmed..Conversely, mutations in genes that adversely affect both respiratory and embryological nodal cilia are a significant cause of heterotaxy and congenital heart disease, and screening for PCD is indicated in those patients. ..
- Horvath J, Fliegauf M, Olbrich H, Kispert A, King S, Mitchison H, et al. Identification and analysis of axonemal dynein light chain 1 in primary ciliary dyskinesia patients. Am J Respir Cell Mol Biol. 2005;33:41-7 pubmed..Based on these findings, we considered DNAL1 a candidate for PCD and sequenced all exons of DNAL1 in 86 patients. Mutational analysis was negative, excluding a major role of DNAL1 in the pathogenesis of PCD. ..
- Bartoloni L, Blouin J, Pan Y, Gehrig C, Maiti A, Scamuffa N, et al. Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia. Proc Natl Acad Sci U S A. 2002;99:10282-6 pubmed..and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome)...
- Leigh M, O Callaghan C, Knowles M. The challenges of diagnosing primary ciliary dyskinesia. Proc Am Thorac Soc. 2011;8:434-7 pubmed publisher..Another chapter in this issue (see Zariwala and colleagues, pp. 430) addresses the progress toward improved capabilities for definitive genetic testing. ..
- Onoufriadis A, Paff T, Antony D, Shoemark A, Micha D, Kuyt B, et al. Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. Am J Hum Genet. 2013;92:88-98 pubmed publisher..One CCDC114 mutation, c.742G>A, dating back to at least the 1400s, presents an important diagnostic and therapeutic target in the isolated Dutch Volendam population. ..
- Zihlif N, Paraskakis E, Tripoli C, Lex C, Bush A. Markers of airway inflammation in primary ciliary dyskinesia studied using exhaled breath condensate. Pediatr Pulmonol. 2006;41:509-14 pubmed..The mechanism of airway neutrophilia is unclear, but is unlikely to be related to increased production of LTB4, at least in stable PCD patients. ..
- Kosaki K, Ikeda K, Miyakoshi K, Ueno M, Kosaki R, Takahashi D, et al. Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality. Am J Med Genet A. 2004;129A:308-11 pubmed..This figure is much higher than the general risk of 1-2% for siblings of a patient with isolated hydrocephalus. ..
- Panizzi J, Becker Heck A, Castleman V, Al Mutairi D, Liu Y, Loges N, et al. CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nat Genet. 2012;44:714-9 pubmed publisher..Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated. ..
- Becker Heck A, Zohn I, Okabe N, Pollock A, Lenhart K, Sullivan Brown J, et al. The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nat Genet. 2011;43:79-84 pubmed publisher..CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD. ..
- O Callaghan C, Chilvers M, Hogg C, Bush A, Lucas J. Diagnosing primary ciliary dyskinesia. Thorax. 2007;62:656-7 pubmed
- Irving S, Ives A, Davies G, Donovan J, Edey A, Gill S, et al. Lung clearance index and high-resolution computed tomography scores in primary ciliary dyskinesia. Am J Respir Crit Care Med. 2013;188:545-9 pubmed publisher..We hypothesize that this results from dissimilarities between the components of large and small airway disease in CF and PCD. These differences may in part lead to the different prognosis in these two neutrophilic airway diseases. ..
- Zariwala M, Noone P, Sannuti A, Minnix S, Zhou Z, Leigh M, et al. Germline mutations in an intermediate chain dynein cause primary ciliary dyskinesia. Am J Respir Cell Mol Biol. 2001;25:577-83 pubmed..Mutations in DNAI1 are causative for PCD with ODA defects, and are likely the genetic origin of clinical disease in some PCD patients with ultrastructural defects in the ODA. ..