Researchers at The Hong Kong University of Science and Technology (HKUST) have uncovered how mutations in a specific gene can trigger a rare respiratory disease, shedding light on the critical role played by cellular structures known as cilia. Cilia are tiny and hair-like organelles extruding from the surface of most cell types, serving either sensory or motile functions. In the eyes, photoreceptor cells possess sensory cilia that are important for vision. Meanwhile, motile cilia align along the surface of the respiratory tract and function in airway clearance of mucus and inhaled pathogens.
Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene affect both photoreceptor sensory cilia and airway motile cilia, leading to retinitis pigmentosa and the rare motile ciliopathy primary ciliary dyskinesia (PCD), respectively. 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, since not all patients with these mutations develop PCD, it has remained unclear which specific RPGR variants predispose patients to the respiratory condition.
To elucidate how the loss of RPGR impacts motile cilia and contributes to respiratory disease, the research team led by Prof. Zhen LIU from the Division of Life Science at HKUST leveraged organoids, super-resolution microscopy, and live-cell imaging. The team investigated nasal multiciliated cells derived from patients carrying RPGR variants, as well as CRISPR-engineered RPGR knockout multiciliated cells. Their study, recently published in the Journal of Clinical Investigation, provides new mechanistic insights into this disease.
In collaboration with physicians from the Hospital for Sick Children and BC Children’s Hospital, Canada, the team analyzed a cohort of 32 patients with different pathological RPGR variants and found that defective and disorganized ciliary structures resulted in impaired ciliary beating or beat coordination. To inspect how RPGR regulates motile cilia, the researchers utilized various super-resolution microscopy modalities, revealing an abnormally condensed apical F-actin meshwork in both patient-derived and RPGR-knockout multiciliated cells. Critically, these ciliary abnormalities could be ameliorated 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. The methodologies and findings hold strong potential clinical applications for diagnosing this rare disease and improving patient outcomes through targeted therapeutic interventions. Furthermore, this study closely supports HKUST’s newly established School of Medicine and reflects the University’s increasing focus on translational medicine.
