An imaging study reveals how gene mutations impair airway clearance and lead to primary ciliary dyskinesia (PCD).
RT’s Three Key Takeaways:
- Genetic Mechanism Identified: Researchers found that mutations in the RPGR gene lead to disorganized ciliary structures and impaired beating, causing the rare respiratory condition primary ciliary dyskinesia.
- Role of F-actin: The study revealed an abnormally condensed apical F-actin meshwork in affected cells, which disrupts the coordination of cilia necessary for clearing mucus and pathogens from the airway.
- Therapeutic Potential: Experimental treatments that disrupted the accumulated F-actin were shown to ameliorate ciliary abnormalities, suggesting a new target for future clinical interventions.
Researchers at The Hong Kong University of Science and Technology (HKUST) have uncovered how mutations in a specific gene trigger a rare respiratory disease called primary ciliary dyskinesia (PCD), highlighting the role of cellular structures called cilia in airway clearance.
Cilia are tiny, hair-like organelles that serve sensory or motile functions. In the respiratory tract, motile cilia align along the surface to clear mucus and inhaled pathogens. Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene affect these structures, leading to the rare motile ciliopathy known as PCD.
Due to the loss of motile cilia function, PCD patients often present with symptoms such as chronic sinusitis, bronchiectasis, recurrent lung infections, heart issues, and infertility. However, because not all patients with these mutations develop the disease, it has remained unclear which specific RPGR variants predispose patients to the respiratory condition.
To investigate how the loss of RPGR impacts motile cilia, a research team led by Zhen Liu, a professor in the division of life science at HKUST, used organoids, super-resolution microscopy, and live-cell imaging. The study, published in the Journal of Clinical Investigation, investigated nasal multiciliated cells from patients carrying RPGR variants as well as engineered knockout cells.
In collaboration with physicians from the Hospital for Sick Children and BC Children’s Hospital in Canada, the team analyzed 32 patients with different pathological RPGR variants. The researchers found that defective and disorganized ciliary structures resulted in impaired ciliary beating or beat coordination.
Super-resolution microscopy revealed an abnormally condensed apical F-actin meshwork in both patient-derived and knockout cells. The study found that these ciliary abnormalities could be improved by treatments that disrupt the accumulated F-actin.
“This study uncovers a distinct role of RPGR in regulating F-actin dynamics at the apical surface, thereby coordinating multiciliogenesis and maintaining proper ciliary beating,” said the researchers, HKUST, in a news release.
The findings suggest potential clinical applications for diagnosing the rare disease and improving patient outcomes through targeted therapeutic interventions. The study also reflects an increasing focus on translational medicine within the HKUST School of Medicine to improve healthcare results for patients with rare respiratory conditions.
