scholarly journals Ciliary Dyneins and Dynein Related Ciliopathies

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1885
Author(s):  
Dinu Antony ◽  
Han G. Brunner ◽  
Miriam Schmidts
Keyword(s):  
Intraflagellar Transport ◽  
Cytoplasmic Dynein ◽  
Vertebrate Development ◽  
Kartagener Syndrome ◽  
Dynein Motor ◽  
Axonemal Dynein ◽  
Ciliary Dyskinesia ◽  
Laterality Defects ◽  
Renal Phenotype ◽  
Ciliary Localization

Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.

scholarly journals Clinical and Genetic Analysis of Children with Kartagener Syndrome

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 900 ◽  
Author(s):  
Rute Pereira ◽  
Telma Barbosa ◽  
Luís Gales ◽  
Elsa Oliveira ◽  
Rosário Santos ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Kartagener Syndrome ◽  
Mucus Clearance ◽  
Pathogenic Variants ◽  
Transmission Electron ◽  
Whole Exome ◽  
Dynein Arms ◽  
Organ Laterality ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes’ products. Our work calls the researcher’s attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families.

scholarly journals The Drosophila orthologue of the primary ciliary dyskinesia-associated gene, DNAAF3, is required for axonemal dynein assembly

2021 ◽  
Author(s):  
Petra zur Lage ◽  
Zhiyan Xi ◽  
Jennifer Lennon ◽  
Iain Hunter ◽  
Wai Kit Chan ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Cell Types ◽  
Drosophila Cell ◽  
Heavy Chains ◽  
Neuron Response ◽  
Dynein Motor ◽  
Assembly Factor ◽  
Axonemal Dynein ◽  
Dynein Arms ◽  
Ciliary Dyskinesia

Ciliary motility is powered by a suite of highly conserved axoneme-specific dynein motor complexes. In humans the impairment of these motors through mutation results in the disease, Primary Ciliary Dyskinesia (PCD). Studies in Drosophila have helped to validate several PCD genes whose products are required for cytoplasmic pre-assembly of axonemal dynein motors. Here we report the characterisation of the Drosophila homologue of the less known assembly factor, DNAAF3. This gene, CG17669 (Dnaaf3), is expressed exclusively in developing mechanosensory chordotonal (Ch) neurons and spermatocytes, the only two Drosophila cell types bearing motile cilia/flagella. Mutation of Dnaaf3 results in larvae that are deaf and adults that are uncoordinated, indicating defective Ch neuron function. The mutant Ch neuron cilia of the antenna specifically lack dynein arms, while Ca imaging in larvae reveals a complete loss of Ch neuron response to vibration stimulus, confirming that mechanotransduction relies on ciliary dynein motors. Mutant males are infertile with immotile sperm whose flagella lack dynein arms and show axoneme disruption. Analysis of proteomic changes suggest a reduction in heavy chains of all axonemal dynein forms, consistent with an impairment of dynein pre-assembly.

Novel Pathogenic DNAH5 Variants in Primary Ciliary Dyskinesia: Association with Visceral Heterotaxia and Neonatal Cholestasis

2021 ◽  
Author(s):  
Hong T. Lin ◽  
Anita Gupta ◽  
Kevin E. Bove ◽  
Sara Szabo ◽  
Fang Xu ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Autosomal Recessive ◽  
Neonatal Cholestasis ◽  
Uncertain Significance ◽  
A Subunit ◽  
Axonemal Dynein ◽  
Infantile Cholestasis ◽  
First Time ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

AbstractThe dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the DNAH5 locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis. Genetic testing indicated that the patient is a compound heterozygote with a pathogenic c.8498G > A (known as pathogenic) on the maternally derived allele and two variants of uncertain significance, c.1206T > A and c.7800T > G, on the paternally derived allele. As PCD is autosomal recessive, we conclude that one, or both, of these paternally derived variants are pathogenic. To our knowledge, this is the first time that the clinical implications of c.1206T > A (p.Asn402Lys) and c.7800T > G (p.Ile2600Met) are documented. Furthermore, we use this case as an example to recommend clinicians to assess for PCD and laterality defects when presented with severe infantile cholestasis. While the association of cholestasis with PCD is relatively uncommon, PCD is a risk factor for increased prevalence of biliary atresia and infections, both of which are known causes of cholestasis in early infancy.

scholarly journals Axonemal Dynein Intermediate-Chain Gene (DNAI1) Mutations Result in Situs Inversus and Primary Ciliary Dyskinesia (Kartagener Syndrome)

2001 ◽  
Vol 68 (4) ◽  
pp. 1030-1035 ◽  
Author(s):  
Cécile Guichard ◽  
Marie-Cécile Harricane ◽  
Jean-Jacques Lafitte ◽  
Philippe Godard ◽  
Marc Zaegel ◽  
...  
Keyword(s):  
Situs Inversus ◽  
Primary Ciliary Dyskinesia ◽  
Chain Gene ◽  
Kartagener Syndrome ◽  
Dynein Intermediate Chain ◽  
Axonemal Dynein ◽  
Ciliary Dyskinesia ◽  
Intermediate Chain

scholarly journals The Drosophila orthologue of the primary ciliary dyskinesia-associated gene, DNAAF3, is required for axonemal dynein assembly

Biology Open ◽  
2021 ◽  
Author(s):  
Petra zur Lage ◽  
Zhiyan Xi ◽  
Jennifer Lennon ◽  
Iain Hunter ◽  
Wai Kit Chan ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Cell Types ◽  
Drosophila Cell ◽  
Heavy Chains ◽  
Neuron Response ◽  
Dynein Motor ◽  
Assembly Factor ◽  
Axonemal Dynein ◽  
Dynein Arms ◽  
Ciliary Dyskinesia

Ciliary motility is powered by a suite of highly conserved axoneme-specific dynein motor complexes. In humans the impairment of these motors through mutation results in the disease, Primary Ciliary Dyskinesia (PCD). Studies in Drosophila have helped to validate several PCD genes whose products are required for cytoplasmic pre-assembly of axonemal dynein motors. Here we report the characterisation of the Drosophila orthologue of the less known assembly factor, DNAAF3. This gene, CG17669 (Dnaaf3), is expressed exclusively in developing mechanosensory chordotonal (Ch) neurons and the cells that generate spermatozoa, the only two Drosophila cell types bearing cilia/flagella containing dynein motors. Mutation of Dnaaf3 results in larvae that are deaf and adults that are uncoordinated, indicating defective Ch neuron function. The mutant Ch neuron cilia of the antenna specifically lack dynein arms, while Ca imaging in larvae reveals a complete loss of Ch neuron response to vibration stimulus, confirming that mechanotransduction relies on ciliary dynein motors. Mutant males are infertile with immotile sperm whose flagella lack dynein arms and show axoneme disruption. Analysis of proteomic changes suggest a reduction in heavy chains of all axonemal dynein forms, consistent with an impairment of dynein pre-assembly.

scholarly journals Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia

2021 ◽  
Vol 22 (15) ◽  
pp. 8272
Author(s):  
Steven K Brennan ◽  
Thomas W Ferkol ◽  
Stephanie D Davis
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Pulmonary Infections ◽  
Disease Research ◽  
The Past ◽  
Clinical Presentations ◽  
Organ Laterality ◽  
Ciliary Dyskinesia ◽  
Laterality Defects ◽  
Severe Lung Disease ◽  
Severe Lung

Primary ciliary dyskinesia (PCD) is a rare inherited condition affecting motile cilia and leading to organ laterality defects, recurrent sino-pulmonary infections, bronchiectasis, and severe lung disease. Research over the past twenty years has revealed variability in clinical presentations, ranging from mild to more severe phenotypes. Genotype and phenotype relationships have emerged. The increasing availability of genetic panels for PCD continue to redefine these genotype-phenotype relationships and reveal milder forms of disease that had previously gone unrecognized.

scholarly journals Functional interaction between dynein light chain and intermediate chain is required for mitotic spindle positioning

2011 ◽  
Vol 22 (15) ◽  
pp. 2690-2701 ◽  
Author(s):  
Melissa D. Stuchell-Brereton ◽  
Amanda Siglin ◽  
Jun Li ◽  
Jeffrey K. Moore ◽  
Shubbir Ahmed ◽  
...  
Keyword(s):  
Light Chain ◽  
Direct Evidence ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Dynein Light Chain ◽  
Spindle Positioning ◽  
Dynein Motor ◽  
Intermediate Chains ◽  
Activator Complex

Cytoplasmic dynein is a large multisubunit complex involved in retrograde transport and the positioning of various organelles. Dynein light chain (LC) subunits are conserved across species; however, the molecular contribution of LCs to dynein function remains controversial. One model suggests that LCs act as cargo-binding scaffolds. Alternatively, LCs are proposed to stabilize the intermediate chains (ICs) of the dynein complex. To examine the role of LCs in dynein function, we used Saccharomyces cerevisiae, in which the sole function of dynein is to position the spindle during mitosis. We report that the LC8 homologue, Dyn2, localizes with the dynein complex at microtubule ends and interacts directly with the yeast IC, Pac11. We identify two Dyn2-binding sites in Pac11 that exert differential effects on Dyn2-binding and dynein function. Mutations disrupting Dyn2 elicit a partial loss-of-dynein phenotype and impair the recruitment of the dynein activator complex, dynactin. Together these results indicate that the dynein-based function of Dyn2 is via its interaction with the dynein IC and that this interaction is important for the interaction of dynein and dynactin. In addition, these data provide the first direct evidence that LC occupancy in the dynein motor complex is important for function.

scholarly journals Stable tug-of-war between kinesin-1 and cytoplasmic dynein upon different ATP and roadblock concentrations

2020 ◽  
Author(s):  
Gina A. Monzon ◽  
Lara Scharrel ◽  
Ashwin DSouza ◽  
Ludger Santen ◽  
Stefan Diez
Keyword(s):  
Cytoplasmic Dynein ◽  
Gliding Motility ◽  
Force Balance ◽  
Stochastic Simulations ◽  
Transport Systems ◽  
Organelle Transport ◽  
Atp Concentration ◽  
Dynein Motor ◽  
Bidirectional Movement

ABSTRACTThe maintenance of intracellular processes like organelle transport and cell division depend on bidirectional movement along microtubules. These processes typically require kinesin and dynein motor proteins which move with opposite directionality. Because both types of motors are often simultaneously bound to the cargo, regulatory mechanisms are required to ensure controlled directional transport. Recently, it has been shown that parameters like mechanical motor activation, ATP concentration and roadblocks on the microtubule surface differentially influence the activity of kinesin and dynein motors in distinct manners. However, how these parameters affect bidirectional transport systems has not been studied. Here, we investigate the regulatory influence of these three parameter using in vitro gliding motility assays and stochastic simulations. We find that the number of active kinesin and dynein motors determines the transport direction and velocity, but that variations in ATP concentration and roadblock density have no significant effect. Thus, factors influencing the force balance between opposite motors appear to be important, whereas the detailed stepping kinetics and bypassing capabilities of the motors have only little effect.

Sign in / Sign up

Export Citation Format

Share Document