Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus

Ibañez–Tallon, Inés; Gorokhova, Svetlana; Heintz, Nathaniel

doi:10.1093/hmg/11.6.715

Cited by 221 publications

(159 citation statements)

References 29 publications

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“…We have not only confirmed that the iv model has static respiratory cilia at 37 • C, but that it develops PCD-related disease including rhinitis, sinusitis, and otitis media. Consistent with other PCD mouse models [Ibanez-Tallon et al, 2002;Lee et al, 2008;Tanaka et al, 2004], none of the mice in this study developed significant lung pathology. This is perhaps an agerelated phenomenon (our oldest mice were 42 weeks old), or lack of disease may be associated with the relatively sterile environment of the animal facilities as suggested for CF models [Davidson and Rolfe, 2001].…”

Section: Discussionsupporting

confidence: 90%

“…A significant proportion, including Dnahc5 (MIM# 603335) [Tan et al, 2007], Poll (MIM# 606343) [Kobayashi et al, 2002], and Dnaic1 (MIM# 604366) [Ostrowski et al, 2010], demonstrate additional defects, particularly hydrocephalus and cardiac anomalies, reducing their viability and raising significant animal welfare issues. The repeated demonstration that mutation of human PCD loci in the mouse results in hydrocephalus has led some to suggest an underlying difference in physiology [Ibanez-Tallon et al, 2002;Ostrowski et al, 2010]. The nm1054 mouse (MGI: Del(1)1Brk), a six-gene deletion, gives rise to PCD-like upper respiratory pathology, lacks cardiac defects, and only shows hydrocephalus on certain genetic backgrounds.…”

Section: Introductionmentioning

confidence: 99%

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Static respiratory cilia associated with mutations in Dnahc11/DNAH11: A mouse model of PCD

et al. 2011

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Primary ciliary dyskinesia (PCD) is an inherited disorder causing significant upper and lower respiratory tract morbidity and impaired fertility. Half of PCD patients show abnormal situs. Human disease loci have been identified but a mouse model without additional deleterious defects is elusive. The inversus viscerum mouse, mutated at the outer arm dynein heavy chain 11 locus (Dnahc11) is a known model of heterotaxy. We demonstrated immotile tracheal cilia with normal ultrastructure and reduced sperm motility in the Dnahc11 iv mouse. This is accompanied by gross rhinitis, sinusitis, and otitis media, all indicators of human PCD. Strikingly, age-related progression of the disease is evident. The Dnahc11 iv mouse is robust, lacks secondary defects, and requires no intervention to precipitate the phenotype. Together these findings show the Dnahc11 iv mouse to be an excellent model of many aspects of human PCD. Mutation of the homologous human locus has previously been associated with hyperkinetic tracheal cilia in PCD. Two PCD patients with normal ciliary ultrastructure, one with immotile and one with hyperkinetic cilia were found to carry DNAH11 mutations. Three novel DNAH11 mutations were detected indicating that this gene should be investigated in patients with normal ciliary ultrastructure and static, as well as hyperkinetic cilia.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Static respiratory cilia associated with mutations in Dnahc11/DNAH11: A mouse model of PCD

et al. 2011

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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: 77%

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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“…These are genes coding for the dynein axonemal intermediate chain 1 (DNAI1) (8)(9)(10) and the dynein axonemal heavy chain 5 (DNAH5) (11). Loss of function of the murine Dnah5 dynein gene also causes PCD in the mouse (12). Other genes coding for axonemal dyneins, such as the heavy chain DNAH9, the intermediate chain DNAI2, and the light chain LC8, were recently excluded as major causes of PCD (13, 14, † †).…”

mentioning

confidence: 99%

Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia

Bartoloni

Blouin

Pan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

317

211

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Primary ciliary dyskinesia (PCD; MIM 242650) is an autosomal recessive disorder of ciliary dysfunction with extensive genetic heterogeneity. PCD is characterized by bronchiectasis and upper respiratory tract infections, and half of the patients with PCD have situs inversus (Kartagener syndrome). We characterized the transcript and the genomic organization of the axonemal heavy chain dynein type 11 (DNAH11) gene, the human homologue of murine Dnah11 or lrd, which is mutated in the iv͞iv mouse model with situs inversus. To assess the role of DNAH11, which maps on chromosome 7p21, we searched for mutations in the 82 exons of this gene in a patient with situs inversus totalis, and probable Kartagener syndrome associated with paternal uniparental disomy of chromosome 7 (patUPD7). We identified a homozygous nonsense mutation (R2852X) in the DNAH11 gene. This patient is remarkable because he is also homozygous for the F508del allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Sequence analysis of the DNAH11 gene in an additional 6 selected PCD sibships that shared DNAH11 alleles revealed polymorphic variants and an R3004Q substitution in a conserved position that might be pathogenic. We conclude that mutations in the coding region of DNAH11 account for situs inversus totalis and probably a minority of cases of PCD.

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Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus

Cited by 221 publications

References 29 publications

Static respiratory cilia associated with mutations in Dnahc11/DNAH11: A mouse model of PCD

Static respiratory cilia associated with mutations in Dnahc11/DNAH11: A mouse model of PCD

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

Mutations in the DNAH11 (axonemal heavy chain dynein type 11) gene cause one form of situs inversus totalis and most likely primary ciliary dyskinesia

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