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A quantitative super-resolution imaging toolbox for diagnosis of motile ciliopathies

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Science Translational Medicine  18 Mar 2020:
Vol. 12, Issue 535, eaay0071
DOI: 10.1126/scitranslmed.aay0071

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Ciliopathy insights

Primary ciliary dyskinesia (PCD) results from genetic mutations and structural defects that impair the motility of cilia, the cellular protrusions that sweep mucus along the surface of the airway. Here, Liu and colleagues developed a quantitative imaging workflow to improve the diagnosis of PCD. Using super-resolution microscopy on nasal airway cells isolated from patients with PCD, the authors detected mislocalized PCD-related proteins, cellular structural defects, and impairments in ciliary beating. These imaging and analysis methods could help complement standard methods of diagnosis, such as genetic testing, and could provide insight into pathology caused by variants of uncertain significance.


Airway clearance of pathogens and particulates relies on motile cilia. Impaired cilia motility can lead to reduction in lung function, lung transplant, or death in some cases. More than 50 proteins regulating cilia motility are linked to primary ciliary dyskinesia (PCD), a heterogeneous, mainly recessive genetic lung disease. Accurate PCD molecular diagnosis is essential for identifying therapeutic targets and for initiating therapies that can stabilize lung function, thereby reducing socioeconomic impact of the disease. To date, PCD diagnosis has mainly relied on nonquantitative methods that have limited sensitivity or require a priori knowledge of the genes involved. Here, we developed a quantitative super-resolution microscopy workflow: (i) to increase sensitivity and throughput, (ii) to detect structural defects in PCD patients’ cells, and (iii) to quantify motility defects caused by yet to be found PCD genes. Toward these goals, we built a localization map of PCD proteins by three-dimensional structured illumination microscopy and implemented quantitative image analysis and machine learning to detect protein mislocalization, we analyzed axonemal structure by stochastic optical reconstruction microscopy, and we developed a high-throughput method for detecting motile cilia uncoordination by rotational polarity. Together, our data show that super-resolution methods are powerful tools for improving diagnosis of motile ciliopathies.

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