Absence Of Dynein Arms Research Articles

To beat, or not to beat, that is question! The spectrum of ciliopathies.

Cilia are widely distributed throughout the human body, and have numerous roles in physiology, development, and disease. Ciliary ultrastructure is complex, consisting of nine parallel microtubules doublets, with or without motor dynein arms and a central pair of microtubules. Classification of cilia has evolved over time, and currently, four main classes are described: motile and non-motile cilia with a "9 + 2" structure, and motile and non-motile cilia with a "9 + 0" structure, which depend on the presence or absence of dynein arms and a central pair. Ciliopathies are inherited multisystem disorders of cilia, and may present with a varied spectrum of genotypes and phenotypes. Motor and sensory ciliopathies were historically considered as distinct dysfunctions of motile and non-motile cilia, but recent data indicate that the classical features of motor and sensory cilia may overlap.

Primary ciliary dyskinesia presentation in 60 children according to ciliary ultrastructure

Primary ciliary dyskinesia (PCD) is an inherited disease related to ciliary dysfunction, with heterogeneity in clinical presentation and in ciliary ultrastructural defect. Our study intended to determine if there are phenotypic differences in patients with PCD based on ciliary ultrastructural abnormality. In this retrospective study carried out among 60 children with a definitive diagnosis of PCD, we analyzed clinical, radiological, and functional features at diagnosis and at last recorded visit, according to cilia defect (absence of dynein arms: DAD group, n = 36; abnormalities of the central complex: CCA group, n = 24). Onset of respiratory symptoms occurred later in the CCA than in the DAD group (9.5 versus 0.5 months, p = 0.03). Situs inversus was only observed in the DAD group, while respiratory disease in siblings were more frequent in the CCA group (p = 0.003). At diagnosis, clinical presentation was more severe in the CCA group: frequency of respiratory tract infections (p = 0.008), rhinosinusitis (p = 0.02), otitis complications (p = 0.0001), bilateral bronchiectasis (p = 0.04), and number of hypoxemic patients (p = 0.03). Pulmonary function remained stable in both groups, but outcome was better in the CCA than in the DAD group: less antibiotic therapy and hypoxemic patients (p = 0.004). In conclusion, our results underlined the relationship between the severity of clinical presentation and the ultrastructural ciliary defect.

Evidencia de transmisión autosómica dominante a través de la línea materna en un caso de discinesia ciliar primaria

An atypical case of primary ciliary dyskinesia is presented in which the inheritance, rather than the classical autosomal recessive, appears to be transmitted as an autosomal dominant trait through the maternal line. The case involves two brothers of 29 and 30 years of age, married without children, with a history of infertility, frequent episodes of sinusitis, and recurrent pulmonary infections. Their mother and sister have chronic bronchopathy of unknown etiology. Their father is healthy without pulmonary problems or sinusitis. At physical exam, both brothers, sister and mother presented with bronchial rhonchi at lung auscultation. Blood analysis and pulmonary function, liver and renal tests were all normal. The ultraestructual study of the sperm flagellum by electron microscopy revealed that both brothers have the same anomaly. Namely, in the majority of the cross-sections, both dynein arms are missing. The nexin filament was present, as well as the radial spokes and the central pair of microtubules. In some sperm, besides the absence of dynein arms, there was also absence of the central pair of microtubules. Neither anomalies of the fibrous sheath nor of the dense fibers were found. In approximately 50% of the spermatozoa, the midpiece had a decreased number of mitochondria and extra non- aligned mitochondria. Other findings included extra peripheral microtubules in the axoneme

Specific Features of Centriole Formation and Ciliogenesis in Ciliary Epithelium Cells of Respiratory Tracts in Patients with Kartagener Syndrome

An electron microscopic study of the ciliary epithelium of respiratory tracts was carried out in children (members of the same family) with Kartagener syndrome, which is a variant of ciliary dyskinesia. It was shown that in the case of both mobile cilia and ciliary dyskinesia in man, centrioles are formed during formation of the ciliary basal bodies predominantly de novo, involving deuterosomes. A wide spectrum of pathological changes was described in literature, such as the absence of dynein arms in the axoneme and disorganization of axoneme structure. In addition to these changes in the ciliary system, we found integration of several ciliary axonemes by the same plasma membrane, running of microtubules from the plasma membrane as bundles, different orientation of basal legs, etc.

Study of Mucociliary Transport and Nasal Ciliary Ultrastructure in Patients With Kartagener's Syndrome

Kartagener's syndrome (KS) is a clinical variant of primary ciliary dyskinesia involving situs inversus associated with chronic airway infections. The ciliary defect associated with this syndrome is the absence of dynein arms. The aim of this study was to evaluate mucociliary transport and ciliary ultrastructure in 14 patients with KS. We studied nasal mucociliary transport using a radioisotopic technique and ciliary ultrastructure in 14 patients with KS. Thirteen patients had mucociliary stasis and 1 had severely slowed transport (1.3 mm/min). Four patients (29%) had cilia with normal dynein arms, 2 patients (14%) had short inner dynein arms, and 8 patients (57.1%) had total absence of inner and outer dynein arms. We conclude that the typical clinical presentation, together with altered mucociliary transport as identified by an isotopic technique, is diagnostic of KS, even when the ciliary ultrastructure is normal. KS is clinically homogenous and morphologically heterogenous.

Improved ventilatory function associated with relief of chest pain in a patient with Kartagener's syndrome treated by subcutaneous analgesia

Kartagener’s syndrome was defined in 1933 as a distinctive clinico-pathological entity characterized by a triad of signs: situs inversus, bronchiectasis and paranasal sinusitis. The condition is a part of the syndrome of primary ciliary dyskinesia, where 50% of the patients have a situs inversus totalis. In primary ciliary dyskinesia, inflammation is not restricted to the ciliated conducting airways, but also occurs in the alveolar space. Repetitive episodes of pleuritic chest pain are a feature of patients with bronchiectasis and middle lobe syndrome. Pleuritic chest pain can occur in up to 21% of patients with bronchiectasis and 19% of patients with middle lobe syndrome and characteristically occurs in an area overlying a bronchiectatic lobe. This presentation can be confused with other conditions, such as pulmonary embolus. However, the natural history of pleuritic chest pain and its response to analgesia in these conditions is poorly described. We report a patient with Kartagener’s syndrome with intractable pleuritic chest pain, in whom peripheral nerve stimulation with subcutaneous electrodes led to a dramatic therapeutic response. Case report

Abnormal central complex is a marker of severity in the presence of partial ciliary defect.

Ciliary ultrastructural defects with total lack of dynein arms (DA) cause abnormal mucociliary function leading to the chronic infections observed in primary ciliary dyskinesia. The role of partial ciliary ultrastructural defects, especially those involving the central complex, and their relationship with respiratory symptoms have been less thoroughly investigated. In a pediatric population with partial ciliary defects, we determined the relationship(s) between ultrastructural findings, ciliary motility, and clinical and functional features, and evaluated the outcome of this population. We analyzed the clinical presentation and pulmonary function of 43 children with chronic bronchitis and partial ultrastructural defects (from 15% to 90%) of their respiratory cilia demonstrated on bronchial biopsies. The study population was divided into 3 groups according to ciliary ultrastructure: the main ultrastructural defect concerned the central complex in 23 patients (CC group), peripheral microtubules in 8 patients (PMT group), and DA in 12 patients (DA group). The percentage of ciliary defects was lower in the PMT group than in the CC and DA groups. Patients in the PMT group had less severe disease with frequent normal ciliary motility. Patients in the CC group had initially a higher incidence of respiratory tract infections, extensive bronchiectasis frequently requiring surgery, and arguments in favor of a congenital origin (high proportion of sibling form). Partial absence of DA, although of congenital origin, was associated with a good prognosis. In all groups, follow-up showed that the functional prognosis remained good with appropriate treatment. In children with chronic respiratory infections, presence of situs inversus, sibling form, obstructive pulmonary syndrome, or bronchiectasis required ultrastructural analysis, regardless of ciliary motility. Detection of CC abnormalities is a marker of severity and required intensive therapy and close follow-up.

The human dynein intermediate chain 2 gene (DNAI2): cloning, mapping, expression pattern, and evaluation as a candidate for primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease characterized by chronic sinusitis and bronchiectasis, and usually associated with hypofertility. Half of the patients present a situs inversus, defining the Kartagener's syndrome. This phenotype results from axonemal abnormalities of respiratory cilia and sperm flagella, i.e., mainly an absence of dynein arms. Recently, a candidate-gene approach, based on documented abnormalities of immotile strains of Chlamydomonas reinhardtii, allowed us to identify the first gene involved in PCD. Following the same strategy, we have characterized DNAI2, a human gene related to Chlamzydomonas IC69, and evaluated its possible involvement in a PCD population characterized by an absence of outer dynein arms. DNAI2, which is composed of 14 exons located at 17q25, is highly expressed in trachea and testis. No mutation was found in the DNAI2 coding sequence of the twelve patients investigated. However, ten intragenic polymorphic sites and an EcoRI RFLP have been identified, allowing the exclusion of DNAI2 in three consanguineous families.

Loss-of-Function Mutations in a Human Gene Related to Chlamydomonas reinhardtii Dynein IC78 Result in Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a group of heterogeneous disorders of unknown origin, usually inherited as an autosomal recessive trait. Its phenotype is characterized by axonemal abnormalities of respiratory cilia and sperm tails leading to bronchiectasis and sinusitis, which are sometimes associated with situs inversus (Kartagener syndrome) and male sterility. The main ciliary defect in PCD is an absence of dynein arms. We have isolated the first gene involved in PCD, using a candidate-gene approach developed on the basis of documented abnormalities of immotile strains of Chlamydomonas reinhardtii, which carry axonemal ultrastructural defects reminiscent of PCD. Taking advantage of the evolutionary conservation of genes encoding axonemal proteins, we have isolated a human sequence (DNAI1) related to IC78, a C. reinhardtii gene encoding a dynein intermediate chain in which mutations are associated with the absence of outer dynein arms. DNAI1 is highly expressed in trachea and testis and is composed of 20 exons located at 9p13-p21. Two loss-of-function mutations of DNAI1 have been identified in a patient with PCD characterized by immotile respiratory cilia lacking outer dynein arms. In addition, we excluded linkage between this gene and similar PCD phenotypes in five other affected families, providing a clear demonstration of locus heterogeneity. These data reveal the critical role of DNAI1 in the development of human axonemal structures and open up new means for identification of additional genes involved in related developmental defects.

Clinical and ultrastructural correlations in nasal mucociliary function observed in children with recurrent airways infections

A study was made of 106 children between 1 and 15 years of age (mean 6 years) with recurrent upper and lower airways infections since birth. Nasal mucociliary transport (NMT) velocity was determined in all subjects by the Tc99m-labeled seroalbumin technique. In 42 children, NMT was found to be altered. In this group of patients the technique was repeated in a period of between 1 and 2 years later. In 23 cases (55%) transport had normalized, while in 19 (45%) it remained altered. Recurrent pneumonia and constant rhinorrhea were more frequent in this group. Situs inversus was only detected in 2 of these patients. Pathology showed ciliary ultrastructure, the absence of dynein arms and microtubule alterations. The absence of cilia was observed in some patients. Normal cilia were also encountered in children with persistently altered nasal mucociliary transport.

Do Nasal Ciliary Changes Reflect Bronchial Changes?: An Ultrastructural Study

Ciliary dyskinesia is characterized by recurrent respiratory tract infections secondary to abnormal ciliary structure and function. The diagnosis of ciliary dyskinesia is based on the detection of axonemal ultrastructural abnormalities (AUA) is respiratory mucosa samples. In most cases, the diagnosis of AUA is made on samples obtained from nasal ciliated cells with little discomfort to the patient. However, no studies have been performed in the same patient to confirm whether nasal samples reflect bronchial ciliary changes. To answer this question and to determine whether it is necessary to sample bronchial cells for the diagnosis of ciliary dyskinesia, we investigated 12 patients (between the age of 5 and 63 yr) with chronic sputum production. The presence of situs inversus, bronchiectasis, chronic sinusitis, and sterility was investigated to determine an inherited disorder. Two groups were established: Group 1 = six patients with an inherited disorder and Group 2 = six patients without evidence of an inherited disorder. Samples were obtained by brushing or biopsy of nasal and bronchial mucosa and were processed for transmission electron microscopy. In Group 1, the mean AUA was 65.2 +/- 11.4%. The following predominant axonemal defects were found: absence of dynein arms (DA) (four patients), central complex abnormalities (CC) (one patient), and various AUA (one patient). Nasal and bronchial samples correlated significantly for total AUA (r' = 1, p < 0.01) and for outer DA defects (r' = 0.96, p < 0.05). A good but not significant correlation was found for inner DA (r' = 0.83) and peripheral microtubule (PM) defects (r' = 0.71). In Group 2, the mean AUA was 9.6 +/- 2.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Ciliary ultrastructure in a child with Kartagener's syndrome

Kartagener's syndrome has been characterized by a primary ultrastructural abnormality of the cilia which consequently impairs their movements. We used transmission electron microscopy with tannic acid staining to investigate the fine structure of the cilia from the nasal mucosa of a 7-year-old girl with Kartagener's syndrome. The staining technique employed was useful for visualizing the dynein arms and protofilaments of the microtubules of the cilia. Although 15% of the cilia examined demonstrated microtubular disarrangements, these findings were considered to be acquired changes due to chronic sinusitis. No abnormal ciliary ultrastructures specific to Kartagener's syndrome, such as absence of dynein arms, were detected in this study. In such cases without any abnormal ciliary ultrastructures, it is conceivable that some other unknown factor may be involved in the impaired ciliary movement.

Kartagener's syndrome: A genetic defect affecting the function of cilia

Kartagener's syndrome, originally described as situs inversus, bronchiectasis, and sinusitis, has recently been demonstrated to be the result of a genetic defect manifest in structural and functional abnormalities of cilia. The absence of dynein arms in the cilia of patients with Kartagener's syndrome has been found be several investigators, utilizing electron microscopy. The cilia of four siblings, two with the syndrome and two without it, were studied by this method. The siblings with Kartagener's syndrome had specific abnormalities of the cilia and the normal siblings did not. The pathophysiology of the disease is discussed and applied to the evaluation and management of patients with Kartagener's syndrome and the immotile cilia syndrome.

Immotile cilia syndrome in persons with and without Kartagener's syndrome.

We studied the ultrastructure and function of respiratory tract cilia in a group of patients with Kartagener's Syndrome, and compared the results with those from a group of subjects with unexplained histories of chronic bronchiectasis and bronchitis. Both patient groups lacked pulmonary and nasal mucociliary transport. On electron microscopic examination of nasal mucosal biopsy tissue, all patient specimens had abnormal cilia with a highly disorganized microtubular network, and a consistent absence of dynein arms. Cilia from both groups were immotile when viewed under direct phase contrast, but could be animated by the addition of 10(-6) g/ml of ATP or ATPase to the same degree of spontaneous motility seen in normal cilia. Immotile cilia syndrome clearly includes not only patients with Kartagener's syndrome, but also some patients with chronic bronchitis and bronchiectasis.

The Immotile Cilia Syndrome: Phase Contrast Light Microscopy, Scanning and Transmission Electron Microscopy

In the immotile cilia syndrome, transmission electron microscopy of the cilia shows abnormalities in the arrangement of the central pairs of tubules and in the dynein arms of the peripheral tubules, or in the radial spokes, We studied four nonrelated children, 9/12, 5, 6, and 6 years old, with situs inversus and a history of chronic sinusitis and bronchitis (Kartagener's syndrome) and four children in the same age group and with the same history, but without situs inversus. Under the phase contrast microscope no motile cilia were seen in the four patients with Kartagener's syndrome and in two of the four other children. Transmission electron microscopy showed aberrations in the cilia (absence of dyneim arms, random orientation of central tubules) in the patients with Kartagener's syndrome. Scanning electron microscopy revealed differences in morphology and arrangement of cilia between patients and controls. In the patients much more mucus was present on the mucosal surface. Furthermore, the cilia were in a state of disorder, with a multidirectional orientation instead of the parallel orientation seen in controls.

Fertility of a Woman with Nonfunctional Ciliated cells in the Fallopian Tubes

Clinical proof is presented to support the conclusion that ciliary movement in the oviduct is probably not essential for female fertility. The patient reported is the same fertile woman (gravida 2 with the complete Kartageners triad) in whom the absence of dynein arms in the axonema of ciliated endocervical cells was reported. 1 year later the woman needed tubal ligation for contraceptive purposes. The fimbrial portion of the fallopian tube which was excised at the time of transvaginal tubal ligation was processed for electron microscopy. On cross-sections of cilia dynein arms were absent. An irregular lateral extension was seen attached to some of the doublets in some cilia. These extensions did not correspond to dynein arms. The random orientation of the central doublets was another indication that these cilia were nonfunctional. The results obtained in this fertile woman confirm a previous study and demonstrate that in women ciliary movement in the fallopian tubes is not essential for fertility.

Absence of Dynein Arms in Cilia of Endocervical Cells in a Fertile Woman

Absence of Dynein Arms in Cilia of Endocervical Cells in a Fertile Woman

912 CILIARY MORPHOLOGY AND CARDIAC MALROTATION

Kartagener's syndrome [situs inversus totalis (SIT), bronchiectasis and sinusitis] has been shown by others to have morphologically abnormal sperm tails and cilia, evidenced by absence of dynein arms. We used brush biopsies of the nasopharynx under local anesthesia for the study of ciliary morphology by EM in 9 patients with dextrocardia. Three of these have SIT and recurrent respiratory disease. One SIT lacks dynein arms and is a typical Kartagener's syndrome. A second SIT has abnormal (thickened and knobby) outer dynein arms in all cilia. This may be a new type of Kartagener's syndrome. The third SIT has normal dynein arms and some features of cystic fibrosis (CF), with intermittently elevated sweat sodium. The cultured fibroblasts of this patient do not show a CF-like response to ouabain, suggesting that this may not be CF. Of the 6 dextrocardiacs without SIT, all have normal dynein arms except one. In this patient (with L-TGA and without respiratory disease), the outer dynein arms are abnormally positioned in all cilia. We propose that dynein arm abnormalities may be an etiologic factor in a significant fraction of cardiac malrotations.