Primary ciliary dyskinesia: a big data genomics approach

Mitchison, Hannah M.; Smedley, Damian

doi:10.1016/s2213-2600(22)00009-1

Cited by 8 publications

(5 citation statements)

References 12 publications

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“…This study contributes to the understanding of genetic causes of PCD by identification of a causative loss of function (LoF) mutation in CFAP300 in Finnish PCD patients. Population specific mutations play an important role in PCD and thus it is important to investigate the genetic variability in different populations (Fassad et al, 2020;Mitchison and Smedley, 2022). We also show that additional to a role in the cytoplasmic preassembly of dynein arms, human CFAP300 is involved in protein transport to motile cilia, which was previously only suggested in model organisms.…”

Section: Introductionsupporting

confidence: 56%

CFAP300 mutation causing primary ciliary dyskinesia in Finland

Schultz

Elenius²,

Fassad³

et al. 2022

Front. Genet.

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Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.

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Section: Introductionsupporting

confidence: 56%

CFAP300 mutation causing primary ciliary dyskinesia in Finland

Schultz

Elenius²,

Fassad³

et al. 2022

Front. Genet.

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“…Second, we included children with probable PCD (ie, without requiring a genetic or molecular diagnosis), but we believe that this is important in the context of the: (a) increasing appreciation of the difficulty in diagnosing PCD,34 (b) lack of a universal gold standard, (c) high prevalence of secondary cilia abnormalities in First Nations children, (d) new genetic abnormalities increasingly found in people without the typical PCD phenotype (ie, absence of daily cough, sino-pulmonary disease in early life),52 (e) confirmation of PCD using current diagnostic methods is limited to very high-resource settings and (f) although yet to be confirmed, people who are not of European or North American origin are likely to be more commonly affected by PCD 53. Importantly, we believe including this group will make our results more generalisable globally while not depriving those without a confirmed PCD diagnosis of a potential benefit.…”

Section: Discussionmentioning

confidence: 99%

Reducing exacerbations in children and adults with primary ciliary dyskinesia using erdosteine and/or azithromycin therapy (REPEAT trial): study protocol for a multicentre, double-blind, double-dummy, 2×2 partial factorial, randomised controlled trial

et al. 2022

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IntroductionPrimary ciliary dyskinesia (PCD) is a rare, progressive, inherited ciliopathic disorder, which is incurable and frequently complicated by the development of bronchiectasis. There are few randomised controlled trials (RCTs) involving children and adults with PCD and thus evidence of efficacy for interventions are usually extrapolated from people with cystic fibrosis. Our planned RCT seeks to address some of these unmet needs by employing a currently prescribed (but unapproved for long-term use in PCD) macrolide antibiotic (azithromycin) and a novel mucolytic agent (erdosteine). The primary aim of our RCT is to determine whether regular oral azithromycin and erdosteine over a 12-month period reduces acute respiratory exacerbations among children and adults with PCD. Our primary hypothesis is that: people with PCD who regularly use oral azithromycin and/or erdosteine will have fewer exacerbations than those receiving the corresponding placebo medications. Our secondary aims are to determine the effect of the trial medications on PCD-specific quality-of-life (QoL) and other clinical outcomes (lung function, time-to-next exacerbation, hospitalisations) and nasopharyngeal bacterial carriage and antimicrobial resistance.Methods and analysisWe are currently undertaking a multicentre, double-blind, double-dummy RCT to evaluate whether 12 months of azithromycin and/or erdosteine is beneficial for children and adults with PCD. We plan to recruit 104 children and adults with PCD to a parallel, 2×2 partial factorial superiority RCT at five sites across Australia. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, lung function and nasopharyngeal carriage by respiratory bacterial pathogens and their associated azithromycin resistance.Ethics and disseminationOur RCT is conducted in accordance with Good Clinical Practice and the Australian legislation and National Health and Medical Research Council guidelines for ethical conduct of Research, including that for First Nations Australians.Trial registration numberACTRN12619000564156.

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“…Mutations in more than 50 different genes cause PCD by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT) (11,12). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotypephenotype relationships, and studying the cell biology of cilia (1,6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Despite these findings, we still lack effective treatments, and people with PCD have significant upper and lower airway impairment (6,19,24).…”

Section: Introductionmentioning

confidence: 99%

Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia

Abou Alaiwa,

Hilkin,

Price

et al. 2024

Preprint

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Mutations in more than 50 different genes cause primary ciliary dyskinesia (PCD) by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotype-phenotype relationships, and studying the cell biology of cilia. Despite these important findings, we still lack effective treatments and people with PCD have significant pulmonary impairment. As with many other diseases, a better understanding of pathogenic mechanisms may lead to effective treatments. To pursue disease mechanisms, we used CRISPR-Cas9 to develop a PCD pig with a disrupted DNAI1 gene. PCD pig airway cilia lacked the outer dynein arm and had impaired beating. MCT was impaired under both baseline conditions and after cholinergic stimulation in PCD pigs. Neonatal PCD pigs developed neonatal respiratory distress with evidence of atelectasis, air trapping, and airway mucus obstruction. Despite airway mucus accumulation, lung bacterial counts were similar between neonatal wild-type and PCD pigs. Sinonasal disease was present in all neonatal PCD pigs. Older PCD pigs developed worsening airway mucus obstruction, inflammation, and bacterial infection. This pig model closely mimics the disease phenotype seen in people with PCD and can be used to better understand the pathophysiology of PCD airway disease.

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Primary ciliary dyskinesia: a big data genomics approach

Cited by 8 publications

References 12 publications

CFAP300 mutation causing primary ciliary dyskinesia in Finland

CFAP300 mutation causing primary ciliary dyskinesia in Finland

Reducing exacerbations in children and adults with primary ciliary dyskinesia using erdosteine and/or azithromycin therapy (REPEAT trial): study protocol for a multicentre, double-blind, double-dummy, 2×2 partial factorial, randomised controlled trial

Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia

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