Primary ciliary dyskinesia

Raidt, Johanna; Loges, Niki T.; Olbrich, Heike; Wallmeier, Julia; Pennekamp, Petra; Omran, Heymut

doi:10.1016/j.lpm.2023.104171

Cited by 12 publications

(5 citation statements)

References 193 publications

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“…In humans, pathogenic variants in 58 genes [ 97 ] cause a rare disease called primary ciliary dyskinesia (PCD), characterized by recurrent lung infections, neonatal respiratory distress, bronchiectasis, otitis media, situs inversus/ambiguus, and male infertility [ 2 , 98 , 99 ]. Reports of SSNC or digenic inheritance (DI) with motile cilia genes are rare.…”

Section: Discussionmentioning

confidence: 99%

Gene dosage of independent dynein arm motor preassembly factors influences cilia assembly in Chlamydomonas reinhardtii

Penny,

Dutcher

2024

PLoS Genet

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Motile cilia assembly utilizes over 800 structural and cytoplasmic proteins. Variants in approximately 58 genes cause primary ciliary dyskinesia (PCD) in humans, including the dynein arm (pre)assembly factor (DNAAF) gene DNAAF4. In humans, outer dynein arms (ODAs) and inner dynein arms (IDAs) fail to assemble motile cilia when DNAAF4 function is disrupted. In Chlamydomonas reinhardtii, a ciliated unicellular alga, the DNAAF4 ortholog is called PF23. The pf23-1 mutant assembles short cilia and lacks IDAs, but partially retains ODAs. The cilia of a new null allele (pf23-4) completely lack ODAs and IDAs and are even shorter than cilia from pf23-1. In addition, PF23 plays a role in the cytoplasmic modification of IC138, a protein of the two-headed IDA (I1/f). As most PCD variants in humans are recessive, we sought to test if heterozygosity at two genes affects ciliary function using a second-site non-complementation (SSNC) screening approach. We asked if phenotypes were observed in diploids with pairwise heterozygous combinations of 21 well-characterized ciliary mutant Chlamydomonas strains. Vegetative cultures of single and double heterozygous diploid cells did not show SSNC for motility phenotypes. When protein synthesis is inhibited, wild-type Chlamydomonas cells utilize the pool of cytoplasmic proteins to assemble half-length cilia. In this sensitized assay, 8 double heterozygous diploids with pf23 and other DNAAF mutations show SSNC; they assemble shorter cilia than wild-type. In contrast, double heterozygosity of the other 203 strains showed no effect on ciliary assembly. Immunoblots of diploids heterozygous for pf23 and wdr92 or oda8 show that PF23 is reduced by half in these strains, and that PF23 dosage affects phenotype severity. Reductions in PF23 and another DNAAF in diploids affect the ability to assemble ODAs and IDAs and impedes ciliary assembly. Thus, dosage of multiple DNAAFs is an important factor in cilia assembly and regeneration.

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Section: Discussionmentioning

confidence: 99%

Gene dosage of independent dynein arm motor preassembly factors influences cilia assembly in Chlamydomonas reinhardtii

Penny,

Dutcher

2024

PLoS Genet

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“…Ciliary dyskinesia has been divided into primary (genetic disorders, inherited) and secondary (acquired). Primary ciliary dyskinesia (PCD) is genetically heterogeneous, with more than 50 associated genes to date [39]. Acquired or secondary ciliary dyskinesia are a consequence of a variety of agents' effects that damage the respiratory epithelium, infection being the most important in bronchiectasis.…”

Section: Ciliary Dyskinesiamentioning

confidence: 99%

“…Findings in PCD span from grossly abnormal to very subtle, and could even be impossible to detect [43]. For example, DNAH11 variants present with hyperkinetic and stiff beat pattern, whereas DRC4/GAS8 variants present with a rotational pattern [39]. (2) Transmission electron microscopy analysis, which reliably detect ODA, combined ODA/IDA or tubular disorganization defects, fails to recognize subtle abnormalities of ciliary ultrastructure present in 15-30% of PCD variants.…”

Section: Ciliary Dyskinesiamentioning

confidence: 99%

Nontuberculous Mycobacteria, Mucociliary Clearance, and Bronchiectasis

Retuerto-Guerrero,

López-Medrano,

de Freitas-González

et al. 2024

Microorganisms

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Nontuberculous mycobacteria (NTM) are environmental and ubiquitous, but only a few species are associated with disease, often presented as nodular/bronchiectatic or cavitary pulmonary forms. Bronchiectasis, airways dilatations characterized by chronic productive cough, is the main presentation of NTM pulmonary disease. The current Cole’s vicious circle model for bronchiectasis proposes that it progresses from a damaging insult, such as pneumonia, that affects the respiratory epithelium and compromises mucociliary clearance mechanisms, allowing microorganisms to colonize the airways. An important bronchiectasis risk factor is primary ciliary dyskinesia, but other ciliopathies, such as those associated with connective tissue diseases, also seem to facilitate bronchiectasis, as may occur in Lady Windermere syndrome, caused by M. avium infection. Inhaled NTM may become part of the lung microbiome. If the dose is too large, they may grow excessively as a biofilm and lead to disease. The incidence of NTM pulmonary disease has increased in the last two decades, which may have influenced the parallel increase in bronchiectasis incidence. We propose that ciliary dyskinesia is the main promoter of bronchiectasis, and that the bacteria most frequently involved are NTM. Restoration of ciliary function and impairment of mycobacterial biofilm formation may provide effective therapeutic alternatives to antibiotics.

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“…In humans, pathogenic variants in 58 genes [128] cause a rare disease called primary ciliary dyskinesia (PCD), characterized by recurrent lung infections, neonatal respiratory distress, bronchiectasis, otitis media, situs inversus/ambiguus, and male infertility [2,129,130] . Reports of SSNC or digenic inheritance (DI) with motile cilia genes are rare.…”

Section: Can Double Heterozygosity In Motile Cilia Genes Play a Role ...mentioning

confidence: 99%

Reduced dosage of multiple dynein arm preassembly factors limits cilia regeneration inChlamydomonas reinhardtii

Penny,

Dutcher

2023

Preprint

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Motile cilia are complex organelles comprised of >800 structural proteins. Variants in 58 of these genes cause primary ciliary dyskinesia (PCD) in humans. We used a second-site non-complementation approach in diploidChlamydomonas reinhardtiistrains to investigate whether reduced dosage of different combinations of motile cilia proteins affects cilia growth / regeneration. Temperature-sensitive mutants in intraflagellar transport genes fail to complement in heterozygous diploids at the restrictive temperature, which may be due to poisonous interactions or a reduction in protein levels. Diploid strains heterozygous for 211 double mutant combinations in 21 genes are phenotypically recessive when unperturbed and do not show SSNC. Consequently, we developed a sensitized screen. When protein synthesis is inhibited, cells utilize the existing cytoplasmic pool of proteins, which is insufficient to build full-length cilia. Six double heterozygous strains in dynein arm preassembly factors (DNAAFs)pf13, pf23, wdr92,andoda8regrow cilia that are shorter than wild-type diploids, which suggests that double heterozygosity limits the pool of assembled dynein arms further. We isolated a new null allele (pf23-4)that shows a more severe loss of ODAs and IDAs in cilia than the previously studiedpf23-1hypomorphic allele. We also identified a new role for PF23 in cytoplasmic modification of IC138, protein of the I1/finner dynein arm. In our SSNC assay, thepf23-4allele also exhibits a more severe phenotype thanpf23-1. Whole cell extract immunoblots show a reduction of PF23 protein to one-half of wild-type levels in both single and double heterozygous genotypes. Thepf13mutant shows SSNC with mutants in two outer dynein arm structural proteins, ODA6, andODA9. We suggest that reduction of multiple dynein preassembly factors limits the pool of assembled dynein arms needed for cilia assembly and regeneration. Our data support PF23 as a scaffolding hub protein involved in dynein arm assembly.Author SummaryMotile cilia are essential for movement of cells and fluids. In humans, motile cilia defects cause primary ciliary dyskinesia (PCD), a rare disease characterized by recurring respiratory infections, left-right asymmetry defects, ear infections, and infertility. Many genes are involved in motile cilia function and assembly. We useChlamydomonas reinhardtiito study the effects of changes in protein levels in different combinations of proteins needed for motile cilia. Our results show that the proteins that help fold and assemble the dynein motors in the cytoplasm are sensitive to changes in the dosage of these preassembly factors. Reductions in proteins involved in multiple steps of the pathway prevents efficient dynein preassembly and cilia regeneration under stressful cellular conditions.

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Primary ciliary dyskinesia

Cited by 12 publications

References 193 publications

Gene dosage of independent dynein arm motor preassembly factors influences cilia assembly in Chlamydomonas reinhardtii

Gene dosage of independent dynein arm motor preassembly factors influences cilia assembly in Chlamydomonas reinhardtii

Nontuberculous Mycobacteria, Mucociliary Clearance, and Bronchiectasis

Reduced dosage of multiple dynein arm preassembly factors limits cilia regeneration inChlamydomonas reinhardtii

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