A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia

Duriez, Bénédicte; Duquesnoy, Philippe; Escudier, Estelle; Bridoux, Anne-Marie; Escalier, Denise; Rayet, I; Marcos, Élisabeth; Vojtek, Anne-Marie; Bercher, Jean‐François; Amselem, Serge

doi:10.1073/pnas.0611405104

Cited by 173 publications

(104 citation statements)

References 58 publications

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“…Reduced movement of ciliary beating causes primary ciliary dyskinesia, including Kartagener syndrome, characterized by situs inversus, bronchiectasis, and chronic sinusitis (40). Such dysmotility or immotility of the cilia results from genetic mutations of major components of the axonema such as dyneins (52)(53)(54), DNA polymerase (55), sperm-associated antigen 6 (56), and a thioredoxin family member (57). In this study, we demonstrated that HSF1 is required for maintenance of ciliary beating in various organs such as the nasal cavity, ventricles, trachea, and oviducts.…”

Section: Discussionmentioning

confidence: 76%

Heat Shock Transcription Factor 1 Is Required for Maintenance of Ciliary Beating in Mice

Takaki

Fujimoto

Nakahari

et al. 2007

Journal of Biological Chemistry

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Heat shock transcription factors (HSFs) maintain protein homeostasis through regulating expression of heat shock proteins, especially in stressed conditions. In addition, HSFs are involved in cellular differentiation and development by regulating development-related genes, as well as heat shock genes. Here, we showed chronic sinusitis and mild hydrocephalus in postnatal HSF1-null mice, which are associated with impaired mucociliary clearance and cerebrospinal flow, respectively. Analysis of ciliary beating revealed that the amplitude of the beating was significantly reduced, and ciliary beat frequencies were lower in the respiratory epithelium, ependymal cells, oviduct, and trachea of HSF1-null mice than those of wild-type mice. Cilia possess a common axonema structure composed of microtubules of ␣-and ␤-tubulin. We found a marked reduction in ␣-and ciliary ␤ iv -tubulin in the HSF1-null cilia, which is developmentally associated with reduced Hsp90 expression in HSF1-null mice. Treatment of the respiratory epithelium with geldanamycin resulted in rapid reduction of ciliary beating in a dose-dependent manner. Furthermore, Hsp90 was physically associated with ciliary ␤ iv -tubulin, and Hsp90 stabilizes tubulin polymerization in vitro. These results indicate that HSF1 is required to maintain ciliary beating in postnatal mice, probably by regulating constitutive expression of Hsp90 that is important for tubulin polymerization.Heat shock response is characterized by induction of a set of heat shock proteins (Hsps) 2 and is a fundamental adoptive response in all organisms from bacteria to humans. This response is regulated mostly at the level of transcription by heat shock transcription factors that bind to the heat shock element in eukaryotes (1, 2). Among four HSF family members (HSF1-4), HSF1 plays a key role in heat shock response in mammals, whereas HSF3 does so in avians (3, 4). This HSF-mediated induction of Hsps is required for acquisition of thermotolerance (5-7) and protection of cells from various pathophysiological conditions (8 -11). Inversely, HSF1 also regulates proapoptotic genes to decide on cell death or life in response to stress (12)(13)(14). In addition to the role in heat shock response, HSFs play critical functions in developmental processes such as gamatogenesis and neurogenesis (15)(16)(17)(18)(19)(20), in maintenance of the sensory organs (21-24), and in immune response (25,26). Although the precise mechanisms of how HSFs act in these physiological processes are still unclear, genetic evidence shows that HSFs regulate constitutive gene expression in unstressed cells and tissues (27, 28). Furthermore, it was revealed in sensory and immune cells that HSFs not only maintain protein homeostasis by regulating constitutive expression of Hsps, but are also involved in cell growth and differentiation by regulating expression of cytokines such as interleukin-6, fibroblast growth factors, and LIF (22,24,25). However, we do not know any client protein stabilized by Hsps that is under the control of HSFs...

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Section: Discussionmentioning

confidence: 76%

Heat Shock Transcription Factor 1 Is Required for Maintenance of Ciliary Beating in Mice

Takaki

Fujimoto

Nakahari

et al. 2007

Journal of Biological Chemistry

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“…Two main genes, DNAI1 and DNAH5 have been identified to date [33,34] for PCD with isolated ODA defects and the other identified genes (i.e. RPGR, TXNDC3, DNAH1, DNAI2, KTU, RSPH9 and RSPH4A) concern a few PCD families [35][36][37][38][39][40]. The identification of the ciliary ultrastructural defect by TEM analysis could also be helpful for genetic analysis.…”

Section: Discussionmentioning

confidence: 99%

A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia

Papon¹,

Coste²,

Roudot‐Thoraval³

et al. 2009

European Respiratory Journal

137

134

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Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for the diagnosis of primary ciliary dyskinesia (PCD). We report our extensive experience of TEM analysis in a large series of patients in order to evaluate its feasibility and results.TEM analysis performed in 1,149 patients with suspected PCD was retrospectively reviewed. Biopsies (1,450) were obtained from nasal (44%) or bronchial (56%) mucosa in children (66.5%) and adults (33.5%).TEM analysis was feasible in 71.4% of patients and showed a main defect suggestive of PCD in 29.9%. TEM was more feasible in adults than in children, regardless of the biopsy site. Main defects suggestive of PCD were found in 76.9% of patients with sinopulmonary symptoms and in only 0.4% of patients with isolated upper and 0.4% with isolated lower respiratory tract infections. The defect pattern was similar in children and adults, involving dynein arms (81.2%) 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).In conclusion, TEM analysis is feasible in most patients and is particularly useful for PCD diagnosis in cases of sinopulmonary syndrome of unknown origin.

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“…The majority of the genes identified (table 1) to date for autosomal recessive PCD variants (dynein, axonemal, intermediate chain 1 (DNAI1) and 2 (DNAI2) and heavy chain 5 (DNAH5) and 11 (DNAH11) and thioredoxin domain containing 3 (TXNDC3)) encode outer dynein arm (ODA) components [15][16][17][18][19][20], whereas only one gene (chromosome 14 open reading frame 104 (KTU)) is required for cytoplasmic preassembly of axonemal dyneins [21]. In addition mutations in the two genes, radial spoke head 9 homologue (RSPH9) and 4 homologue A (RSPH4A), have been reported in PCD patients with abnormalities of the central microtubular pair [22].…”

Section: Genetics and Inheritancementioning

confidence: 99%

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children

Barbato¹,

Frischer²,

Kuehni³

et al. 2009

European Respiratory Journal

458

587

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Primary ciliary dyskinesia (PCD) is associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility.The diagnosis of PCD requires the presence of the characteristic clinical phenotype and either specific ultrastructural ciliary defects identified by transmission electron microscopy or evidence of abnormal ciliary function.Although the management of children affected with PCD remains uncertain and evidence is limited, it remains important to follow-up these patients with an adequate and shared care system in order to prevent future lung damage.This European Respiratory Society consensus statement on the management of children with PCD formulates recommendations regarding diagnostic and therapeutic approaches in order to permit a more accurate approach in these patients. Large well-designed randomised controlled trials, with clear description of patients, are required in order to improve these recommendations on diagnostic and treatment approaches in this disease.

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A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia

Cited by 173 publications

References 58 publications

Heat Shock Transcription Factor 1 Is Required for Maintenance of Ciliary Beating in Mice

Heat Shock Transcription Factor 1 Is Required for Maintenance of Ciliary Beating in Mice

A 20-year experience of electron microscopy in the diagnosis of primary ciliary dyskinesia

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children

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