Dynein Dysfunction as a Cause of Primary Ciliary Dyskinesia and Other Ciliopathies

Becker-Heck, Anita; Loges, Niki T.; Omran, Heymut

doi:10.1016/b978-0-12-382004-4.10024-x

Cited by 8 publications

(12 citation statements)

References 163 publications

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“…However, apart from slow motility, there appear to be no other consequences for these unicellular organisms, at least in the laboratory. In contrast, in vertebrates (including humans), ciliary motility and the consequent fluid flow powered by axonemal dyneins, play key roles in development, reproduction, and organismal homeostasis (Fliegauf et al 2007;Becker-Heck et al 2012). Reduction of ciliary beat frequency caused by mutations within axonemal dyneins or their cytoplasmic assembly factors leads to primary ciliary dyskinesia (PCD), which includes multiple phenotypes of varying severity depending on the precise mutational target (Becker-Heck et al 2012).…”

Section: Consequences Of Dynein Arm Dysfunctionmentioning

confidence: 99%

“…In contrast, in vertebrates (including humans), ciliary motility and the consequent fluid flow powered by axonemal dyneins, play key roles in development, reproduction, and organismal homeostasis (Fliegauf et al 2007;Becker-Heck et al 2012). Reduction of ciliary beat frequency caused by mutations within axonemal dyneins or their cytoplasmic assembly factors leads to primary ciliary dyskinesia (PCD), which includes multiple phenotypes of varying severity depending on the precise mutational target (Becker-Heck et al 2012). In general, patients with PCD show highly reduced fertility because of poor sperm motility in males and reduction in beat frequency of the cilia lining the fallopian tubes in females that are involved in oocyte movement toward the uterus.…”

Section: Consequences Of Dynein Arm Dysfunctionmentioning

confidence: 99%

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Axonemal Dynein Arms

King

2016

Cold Spring Harb Perspect Biol

117

125

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Axonemal dyneins form the inner and outer rows of arms associated with the doublet microtubules of motile cilia. These enzymes convert the chemical energy released from adenosine triphosphate (ATP) hydrolysis into mechanical work by causing the doublets to slide with respect to each other. Dyneins form two major groups based on the number of heavy-chain motors within each complex. In addition, these enzymes contain other components that are required for assembly of the complete particles and/or for the regulation of motor function in response to phosphorylations status, ligands such as Ca, changes in cellular redox state and which also apparently monitor and respond to the mechanical state or curvature in which any given motor finds itself. It is this latter property, which is thought to result in waves of motor function propagating along the axoneme length. Here, I briefly describe our current understanding of axonemal dynein structure, assembly, and organization.

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Section: Consequences Of Dynein Arm Dysfunctionmentioning

confidence: 99%

Section: Consequences Of Dynein Arm Dysfunctionmentioning

confidence: 99%

Axonemal Dynein Arms

King

2016

Cold Spring Harb Perspect Biol

117

125

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“…Respiratory cilia are composed of more than 200 proteins (7) that form 9 microtubular doublets arranged around a central microtubulus pair (CP) ( Figure 1A). Dynein chains attached to the A-microtubule, referred to as outer dynein arms (ODA) and inner dynein arms (IDA), promote microtubular sliding through ATPase activity (8).…”

Section: Introductionmentioning

confidence: 99%

Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects

Frommer

Hjeij

Loges

et al. 2015

Am J Respir Cell Mol Biol

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117

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Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating, leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. Individuals with PCD caused by defective radial spoke (RS) heads are difficult to diagnose owing to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most mutations identified in human radial spoke genes (RSPH) are loss-of-function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the RS complex to improve diagnostics in PCD. We report 21 individuals with PCD (16 families) with biallelic mutations in RSPH9, RSPH4A, and RSPH1, including seven novel mutations comprising missense variants, and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with RS defects. Absence of RSPH4A due to mutations in RSPH4A results in deficient axonemal assembly of the RS head components RSPH1 and RSPH9. RSPH1 mutant cilia, lacking RSPH1, fail to assemble RSPH9, whereas RSPH9 mutations result in axonemal absence of RSPH9, but do not affect the assembly of the other head proteins, RSPH1 and RSPH4A. Interestingly, our results were identical in individuals carrying loss-of-function mutations, missense variants, or one amino acid deletion. Immunofluorescence analysis can improve diagnosis of PCD in patients with loss-of-function mutations as well as missense variants. RSPH4A is the core protein of the RS head.

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“…Motile flagella and cilia are related organelles found on the surface of cells evolutionarily conserved across 1.6 billion years from the flagella of the green alga Chlamydomonas to the ciliated respiratory and embryonic node cells of vertebrates [Pazour, ]. In humans, motile cilia have a common microtubule‐based ultrastructure (axoneme), comprising nine peripheral microtubule doublets either surrounding (in “9+2” motile respiratory and fallopian tube cilia, and sperm flagella) or lacking (in “9+0” motile nodal cilia) a central microtubule pair [Becker‐Heck et al., ; Fliegauf et al., ], and linked to a variety of microtubule‐associated proteins. These include the inner and outer dynein arm (IDA and ODA) motor complexes, which project from the peripheral microtubule doublets; the radial spokes, which provide a radial scaffold between the central pair and peripheral microtubules and facilitate signal transduction from the center out to the dynein arms to govern ciliary beat and waveform [Becker‐Heck et al., ]; and nexin–dynein regulatory complexes (N‐DRC), which attach between adjacent peripheral doublets to facilitate IDA attachment and regulate dynein activity [Heuser et al., ].…”

Section: Introductionmentioning

confidence: 99%

Mutations inCCDC39andCCDC40are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms

et al. 2013

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Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed ‘radial spoke defect’. We sequenced CCDC39 and CCDC40 in 54 ‘radial spoke defect’ families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice and frameshift predicting early protein truncation, which suggests this defect is caused by ‘null’ alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganisation and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as ‘IDA and nexin-dynein regulatory complex (N-DRC) defect’, rather than ‘radial spoke defect’.

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Dynein Dysfunction as a Cause of Primary Ciliary Dyskinesia and Other Ciliopathies

Cited by 8 publications

References 163 publications

Axonemal Dynein Arms

Axonemal Dynein Arms

Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects

Mutations inCCDC39andCCDC40are the Major Cause of Primary Ciliary Dyskinesia with Axonemal Disorganization and Absent Inner Dynein Arms

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