Mutations ofDNAH11in patients with primary ciliary dyskinesia with normal ciliary ultrastructure
Michael R. KnowlesMargaret W. LeighJohnny L. CarsonStephanie D. DavisSharon DellThomas W. FerkolKenneth N. OlivierScott D. SagelMargaret RosenfeldKimberlie A. BurnsSusan L. MinnixMichael C. ArmstrongAdriana LoriMilan J. HazuchaNiki T. LogesHeike OlbrichAnita Becker-HeckMiriam SchmidtsClaudius WernerHeymut OmranMaimoona A. Zariwala
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Abstract:
Rationale
Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11).Objectives
To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology.Methods
82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease.Results
Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations.Conclusions
Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.Keywords:
Compound heterozygosity
Kartagener Syndrome
Ciliopathy
Motile cilium
Axoneme
Background:CEP164 encodes a centrosomal protein required for assembly of primary cilia. More recently it has been suggested it may also have a role in formation of multiple motile cilia. Pathogenic variants in CEP164 are known to cause nephronophthisis-related ciliopathies but a causative link to the motile ciliopathy primary ciliary dyskinesia (PCD) has not been proven. Aim: To assess airway cilia in a patient with a clinical history consistent with PCD, and bi-allelic variants in CEP164. Method: A patient with bronchiectasis in the UK 100,000 Genomes Project was found to have compound heterozygous stop gain variants in CEP164, and no other relevant variants. The patient underwent PCD diagnostic functional testing including high-speed video microscopy and transmission electron microscopy (TEM) of nasal epithelial cells. In addition, localisation of CEP164 protein was assessed by immunofluorescence (IF). Results: Cilia displayed a dyskinetic ciliary beat pattern, with long cilia and cilia with bulbous tips. Air liquid interface culture partially resolved dyskinesia, however an abnormal 'staggered' beat pattern was evident and the presence of long cilia persisted. Ciliary ultrastructure was normal by TEM. IF analysis demonstrated an absence of CEP164 labelling at the centriolar region. Conclusion: Supported by BEAT-PCD, we provide evidence that presence of CEP164 is vital to correct formation and function of respiratory cilia in addition to primary cilia, and that pathogenic variants in CEP164 are responsible for the PCD phenotype in this patient. We suggest CEP164 should be considered a candidate gene for PCD.
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Motile cilium
Ciliopathies
Intraflagellar Transport
Video microscopy
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Primary ciliary dyskinesia (PCD) is a ciliopathy, but represents the sole entity from this class of disorders that results from the dysfunction of motile cilia. Characterized by respiratory problems appearing in childhood, infertility, and situs defects in ~50% of individuals, PCD has an estimated prevalence of approximately 1 in 10,000 live births. The diagnosis of PCD can be prolonged due to a lack of disease awareness, coupled with the fact that symptoms can be confused with other more common genetic disorders, such as cystic fibrosis, or environmental insults that result in frequent respiratory infections. A primarily autosomal recessive disorder, PCD is genetically heterogeneous with >30 causal genes identified, posing significant challenges to genetic diagnosis. Here, we provide an overview of PCD as a disorder underscored by impaired ciliary motility; we discuss the recent advances towards uncovering the genetic basis of PCD; we discuss the molecular knowledge gained from PCD gene discovery, which has improved our understanding of motile ciliary assembly; and we speculate on how accelerated diagnosis, together with detailed phenotypic data, will shape the genetic and functional architecture of this disorder.
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Ciliopathy
Motile cilium
Kartagener Syndrome
Genetic disorder
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Primary ciliary dyskinesia (PCD) is an orphan disease associated with mutations in several genes. It is a ciliopathy, an abnormality of the cilia and flagella. Ciliopathies include the extremely rare Simpson - Golabi - Bemel syndrome (SSGB) type II. The aim of this article is to familiarize the reader with the possibility of simultaneous presence of type II SSGB and PCD in a patient with bronchiectasis (BE). Results. The first clinical observation in the Russian literature is presented withhistory, physical examination, including clinical and morphologic examination, results of additional investigations and initiation of therapy. The case describes a 15-year-old patient with BE and other lesions typical of PCD confirmed on the basis of structural changes in the cilia of the respiratory epithelium of the trachea detected by transmission electron microscopy. The patient had a pathogenic mutation of the OFD1 gene responsible for the development of both type II SSGB and PCD. Conclusion. Several variants of ciliopathies may occur in one patient, and PCD may present as a syndrome.
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Kartagener Syndrome
Bardet–Biedl Syndrome
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Bardet–Biedl Syndrome
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Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.
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Cilia are evolutionarily conserved structures that play a role in diverse cell types. Motile cilia are involved in the most prominent ciliopathy called primary ciliary dyskinesia (PCD), which combines oto-sino-pulmonary symptoms (impaired mucociliary clearance that is important innate defense mechanism), male infertility and in nearly 50% cases situs inversus. Disease is usually inherited as autosomal recessive disorder, concerning mainly outer and/or inner dynein arms of cilia. Diagnosis of PCD requires the presence of characteristic clinical phenotype and confirmation the diagnosis by either identification of specific defect in electron microscopy or other evidence of abnormal ciliary function. The diagnosis of PCD may be delayed, missed or made incorrectly. The first ERS consensus statement which formulates recommendations regarding diagnostic as well as therapeutic approaches to children with PCD, is a very helpful tool in the management of this patients. We present our own experience with three children with PCD diagnosed in our Department.in children with clinical symptoms suggesting PCD, even with negative screening tests, the estimation of specific cilia defect in electron microscopy is indicated.
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Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis.This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing.PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.
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Primary ciliary dyskinesia is an autosomal recessive disorder affecting the motility of cilia. There are a range of ultrastructural ciliary defects that lead to associated clinical symptoms including ineffective mucus clearance, reduced lung function, infertility, and left-right isomerism. Mutations in radial spoke head proteins are a known cause of primary ciliary dyskinesia. Ultrastructually these defects are identified by a portion of cilia lacking a central pair and transposed outer microtubular doublets. We have repeatedly observed an intermittent loss of the central pair in patients with a transposition defect. To further understand the central pair changes in these radial spoke head mutations we employ electron tomography, a high resolution electron microscope technique, to elucidate in three dimensions the ultrastructural arrangements caused by mutation of the RSPH4A gene. We thereby provide an explanation of the structures observed by conventional electron microscopy studies. We demonstrate that the central pair can be present within the cilium. In some cilia, the central pair rotates at the base of the axoneme. We propose that it is this rotation that gives rise to an intermittent appearance of the central pair when viewed under conventional electron microscopy. We discuss the potential causes and consequences of these findings. © 2014 Wiley Periodicals, Inc.
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Mucociliary clearance
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