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Recent Advances in Primary Ciliary Dyskinesia Genetics Małgorzata Kurkowiak,1,2 Ewa Ziętkiewicz,1 Michał Witt1,2

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Recent Advances in Primary Ciliary Dyskinesia Genetics Małgorzata Kurkowiak,1,2 Ewa Ziętkiewicz,1 Michał Witt1,2 JMG Online First, published on October 28, 2014 as 10.1136/jmedgenet-2014-102755 Review J Med Genet: first published as 10.1136/jmedgenet-2014-102755 on 28 October 2014. Downloaded from Recent advances in primary ciliary dyskinesia genetics Małgorzata Kurkowiak,1,2 Ewa Ziętkiewicz,1 Michał Witt1,2 1Department of Molecular and ABSTRACT structures like outer dynein arms (ODAs), inner Clinical Genetics, Institute of Primary ciliary dyskinesia (PCD) is a rare genetically dynein arms (IDAs), nexin-dynein regulatory Human Genetics, Polish Academy of Sciences, Poznań, heterogeneous disorder caused by the abnormal complexes (N-DRCs), radial spokes (RSs)); Poland structure and/or function of motile cilia. The PCD found on the apical surface of epithelial cells in 2International Institute of diagnosis is challenging and requires a well-described the airways (respiratory cilia), brain (ependymal Molecular and Cell Biology, clinical phenotype combined with the identification of cilia), female reproductive system (cilia in fallo- Warsaw, Poland abnormalities in ciliary ultrastructure and/or beating pian tube) or in male reproductive system (sperm fl 5–8 Correspondence to pattern as well as the recognition of genetic cause of agella); Dr Małgorzata Kurkowiak, the disease. Regarding the pace of identification of PCD- ▸ motile cilia with the 9+0 pattern (they lack CP Department of Molecular and related genes, a rapid acceleration during the last but still contain ODAs and IDAs); found in the Clinical Genetics, Institute of 2–3 years is notable. This is the result of new embryo (nodal cilia);910 Human Genetics, Polish technologies, such as whole-exome sequencing, that ▸ non-motile cilia with the 9+2 pattern; found in Academy of Sciences, 32 11 Strzeszyńska Street, Poznań have been recently applied in genetic research. To date, the inner ear (kinocilia); 60-479, Poland; PCD-causative mutations in 29 genes are known and the ▸ non-motile cilia with the 9+0 pattern (no CP [email protected] number of causative genes is bound to rise. Even though and associated structures), acting mainly as the genetic causes of approximately one-third of PCD mechanosensor and chemosensors; they are Received 31 August 2014 12 13 Accepted 8 October 2014 cases still remain to be found, the current knowledge present in kidney (renal cilia), bile duct can already be used to create new, accurate genetic (cholangiocyte cilia),14 pancreas (cilia in pancre- tests for PCD that can accelerate the correct diagnosis atic duct),15 bone or cartilage (cilia in osteocyte and reduce the proportion of unexplained cases. This or chondrocyte)16 17 or in the eye (photorecep- review aims to present the latest data on the relations tor connecting cilia).18 between ciliary structure aberrations and their genetic The ultrastructural elements of cilia are com- basis. posed of many proteins; their definition in human cilia is largely based on the information from Chlamydomonas reinhardtii, a unicellular biflagel- CILIARY STRUCTURE AND PRIMARY CILIARY late green alga.19 A broad knowledge on the func- DYSKINESIA tion of flagellar proteins could be used in the Cilia and flagella are highly evolutionary conserved studies of ciliary proteins thanks to the high evolu- organelles present on the variety of eukaryotic tionary conservation of these organelles. http://jmg.bmj.com/ cells. Axoneme, the core of the cytoskeletal struc- Each peripheral doublet consists of MT A and ture of cilia and flagella, emanates from the basal MT B, built of 13 and 11 protofilaments, respect- body, which is necessary for anchoring the cilium ively; protofilaments are composed of α and β to the apical side of the cell.1 Cilia and flagella are tubulin heterodimers. The MTs A and B of the continuously assembled and disassembled at their neighbouring peripheral doublets interconnect with distal tips. Intraflagellar transport is essential for each other by the N-DRC. From each MT A, ODAs the transport of flagellar/ciliary components from and IDAs extend; both are large force-producing on September 25, 2021 by guest. Protected copyright. the basal body to their assembly region and for the multiprotein complexes (molecular motors).20 removal of turnover products from the flagellar/ ODA complexes face towards the boundary of the ciliary tip. Anterograde (base-to-tip) transport with cilium while IDA complexes are directed towards the heterotrimeric kinesin-2 and retrograde the CP. The peripheral doublets are connected to (tip-to-base) transport with the cytoplasmic dynein the CP via RSs. The CP complex, RSs, IDA iso- – occur at a constant rate without pauses.2 4 forms f (figure 1) and N-DRC are important for – The axoneme consists of microtubule (MT) the coordination of the dynein motor activity.21 23 doublets (figure 1) associated with the large All these components, except ODA, are distributed number of multiprotein components. In humans, with the 96 nm periodicity along the axoneme. axonemes with either 9+2 or 9+0 microtubular ODAs are repeated every 24 nm; in addition, two pattern identified on cross sections are present. In forms of ODA can be distinguished: proximal the 9+2 cilia, nine peripheral MT doublets sur- (characterised by the presence of two heavy dynein round a central pair (CP) of MTs, while in the 9+0 chains, DNAH5 and DNAH9) and distal, which do cilia no CP is present. Cilia can be divided into two not contain DNAH9.24 major groups: motile and non-motile (primary). To cite: Kurkowiak M, Subgroups with different ultrastructural patterns CLINICAL FEATURES AND DIAGNOSIS OF PCD Ziętkiewicz E, Witt M. J Med Genet Published Online First: can be distinguished depending on the structure A wide range of different functions played by cilia [please include Day Month and function they perform: present on nearly all types of vertebrate cells under- Year] doi:10.1136/ ▸ motile cilia with the 9+2 pattern (nine periph- lies their importance in the functioning of the jmedgenet-2014-102755 eral microtubular doublets, CP and associated organism. Symptoms triggered by dysfunctional Kurkowiak M, et al. J Med Genet 2014;0:1–9. doi:10.1136/jmedgenet-2014-102755 1 Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence. Review J Med Genet: first published as 10.1136/jmedgenet-2014-102755 on 28 October 2014. Downloaded from Figure 1 Schematic diagram of the ciliary axoneme in Chlamydomonas. Upper left: longitudinal section of a cilium presenting the location of axonemal microtubules in different parts of the cilium. Red line indicates the site of a cross section presented on the right site. The cross section shows nine microtubule doublets surrounding the central pair of microtubules. The microtubules are interconnected via radial spokes, N-DRCs and dynein arms; no dynein arms are present in the transition region. All these structures except ODA are distributed with the 96 nm periodicity along the axoneme; ODA are present every 24 nm. The placement of all these structures in relation to each other within the 96 nm repeat is depicted at the bottom. a/d, b/g, c and e, single-headed IDA isoforms; fα and fβ, double-headed IDA isoform f; IC/LC, intermediate chain-light chain complex of inner dynein arms (IDA); Mt A, microtubule A; Mt B, microtubule B; N-DRC, nexin-dynein regulatory complex; ODA, outer dynein arms with marked α, β and γ heavy chains; RS1, radial spoke 1, RS2; radial spoke 2; RS3S, radial spoke 3 stump. Scheme based on the original data published http://jmg.bmj.com/ previously.98 cilia form a broad and phenotypically heterogeneous category bronchiectasis or chronic lung disease.31 32 PCD symptoms of overlapping disorders, commonly named ciliopathies. involve organs where motility of cilia has an impact on their Primary ciliary dyskinesia (PCD, OMIM id: 242650), a rare, normal functioning. The most prominent PCD features relate to genetically heterogeneous autosomal-recessive disease, is the the upper and lower respiratory tract and usually appear early major ciliopathy related to the dysfunction of motile cilia. The after birth. Those symptoms include neonatal respiratory dis- on September 25, 2021 by guest. Protected copyright. incidence of PCD is estimated at 1:10 000–1:20 000 live tress syndrome, which comprises chest congestion, coughing, births.25 26 Extrapolating these data, approximately 70 new tachypnoea (rapid breathing) and hypoxia.31 32 In cases where cases can be born each year in the white population dextrocardia, situs ambiguous or situs inversus are present in worldwide.27 the infant, PCD should be considered as a highly possible diag- The history of PCD dates back to 1904 when nosis.33 34 Later, chronic sinusitis and secretory otitis media Dr A. K. Siewert reported the coexistence of bronchiectasis and might occur, which, together with chronic middle ear effusion, – situs inversus.28 A few decades later, in 1933, Manes Kartagener frequently lead to hearing loss.35 37 There are also lower described multiple cases with bronchiectasis, situs inversus and respiratory tract symptoms like wheezing, chronic wet cough sinusitis and named this disorder the Kartagener syndrome.29 frequently with sputum production, chronic bronchitis and Then in 1976, Björn Afzelius, using transmission electron recurrent pneumonia; after several years these symptoms may microscopy (TEM), identified an absence of dynein arms in the lead to bronchiectasis in the middle and lower lobes.27 Upper axoneme of respiratory cilia and sperm flagella in patients with respiratory tract abnormalities include persistent rhinitis, Kartagener syndrome. He concluded that the observed lack of mucosal congestion, nasal passages oedema and infrequently dynein arms must be the cause of ciliary immotility leading to (more prevalent in adults) nasal polyps.38 In older children and all symptoms of Kartagener syndrome including male infertility adults, chronic and recurrent sinusitis as well as chronic muco- due to azoospermia.30 purulent sputum production are common features.
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