Hong Kong — Researchers at the Hong Kong University of Science and Technology (HKUST) have revealed how mutations in a single gene can spark a rare respiratory disorder, highlighting the essential role of cellular structures known as cilia.

Cilia are microscopic, hair-like organelles that extend from the surface of most cells, serving either sensory or motile functions. In the eye, photoreceptor cells rely on sensory cilia for vision. In the respiratory tract, motile cilia line the airway, working in synchrony to clear mucus and inhaled pathogens.

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene disrupt both photoreceptor sensory cilia and airway motile cilia. This leads to two distinct conditions: retinitis pigmentosa, a degenerative eye disease, and primary ciliary dyskinesia (PCD), a rare motile ciliopathy.

PCD patients often suffer from chronic sinusitis, bronchiectasis, recurrent lung infections, heart complications, and infertility. Yet intriguingly, not all individuals with RPGR mutations develop PCD, leaving unanswered which specific variants predispose patients to respiratory disease.

To address this, a team led by Prof. Zhen LIU from HKUST’s Division of Life Science employed organoids, super-resolution microscopy, and live-cell imaging. They studied nasal multiciliated cells derived from patients carrying RPGR variants, alongside CRISPR-engineered RPGR knockout cells. Their findings, published in the Journal of Clinical Investigation, provide fresh mechanistic insights into how RPGR loss impacts motile cilia.

Working with physicians from the Hospital for Sick Children and BC Children’s Hospital in Canada, the team analyzed 32 patients with different RPGR mutations. They discovered that defective and disorganized ciliary structures impaired both the strength and coordination of ciliary beating. Further imaging revealed an abnormally condensed apical F-actin meshwork in patient-derived and knockout cells. Importantly, treatments that disrupted this excess F-actin restored healthier ciliary function.

The study establishes a distinct role for RPGR in regulating F-actin dynamics at the apical surface, ensuring proper multiciliogenesis and coordinated ciliary beating. These insights open new avenues for clinical diagnosis and targeted therapies for PCD.

Beyond its scientific impact, the work underscores HKUST’s growing emphasis on translational medicine and aligns with the mission of its newly established School of Medicine.