scholarly journals A null allele of Dnaaf2 displays embryonic lethality and mimics human ciliary dyskinesia

2019 ◽  
Vol 28 (16) ◽  
pp. 2775-2784 ◽  
Author(s):  
Agnes Cheong ◽  
Rinat Degani ◽  
Kimberly D Tremblay ◽  
Jesse Mager
Keyword(s):  
Genetic Background ◽  
Primary Ciliary Dyskinesia ◽  
Null Allele ◽  
Mouse Embryos ◽  
International Mouse Phenotyping Consortium ◽  
Assembly Factor ◽  
Dynein Arms ◽  
Ciliary Dyskinesia ◽  
Laterality Defects

Abstract The dynein axonemal assembly factor (Dnaaf) protein family is involved in preassembly and stability of dynein arms before they are transported into the cilia. In humans, mutations in DNAAF genes lead to several diseases related to cilia defects such as primary ciliary dyskinesia (PCD; OMIM: 612518). Patients with PCD experience malfunctions in cilia motility, which can result in inflammation and infection of the respiratory tract among other defects. Previous studies have identified that a mutation in DNAAF2 results in PCD and that 40% of these patients also experience laterality defects. In an outbred genetic background, Dnaaf2 homozygotes die after birth and have left/right defects among other phenotypes. Here we characterize a novel null allele of Dnaaf2 obtained from the International Mouse Phenotyping Consortium. Our data indicate that on a defined C57bl/6NJ genetic background, homozygous Dnaaf2 mouse embryos fail to progress beyond organogenesis stages with many abnormalities including left–right patterning defects. These findings support studies indicating that hypomorphic mutations of human DNAAF2 can result in ciliary dyskinesia and identify Dnaaf2 as an essential component of cilia function in vivo.

scholarly journals Mutations in the dynein assembly factor PF22 (DNAAF3) cause primary ciliary dyskinesia with absent dynein arms

Cilia ◽  
2012 ◽  
Vol 1 (S1) ◽  
Author(s):  
M Schmidts ◽  
J Freshour ◽  
NT Loges ◽  
A Dritsoula ◽  
D Antony ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Assembly Factor ◽  
Dynein Arms ◽  
Ciliary Dyskinesia

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.

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 Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms

2018 ◽  
Vol 102 (5) ◽  
pp. 973-984 ◽  
Author(s):  
Inga M. Höben ◽  
Rim Hjeij ◽  
Heike Olbrich ◽  
Gerard W. Dougherty ◽  
Tabea Nöthe-Menchen ◽  
...  
Keyword(s):  
Primary Ciliary Dyskinesia ◽  
Body Asymmetry ◽  
Dynein Arms ◽  
Ciliary Dyskinesia

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.

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