CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia

Area of Science:

• Genetics
• Cell Biology
• Respiratory Medicine

Background:

• Primary ciliary dyskinesia (PCD) is a genetic disorder affecting cilia function, leading to chronic sinopulmonary disease.
• Current diagnostic methods often rely on identifying ciliary ultrastructural abnormalities and immotile cilia.
• The genetic underpinnings of PCD are continually being discovered.

Purpose of the Study:

• To identify novel genetic causes of PCD.
• To investigate a new gene associated with PCD that presents without typical ultrastructural defects.
• To elucidate the role of the identified gene in ciliary function.

Main Methods:

• Genetic linkage analysis in a family with PCD.
• Gene expression studies in Chlamydomonas reinhardtii and human airway epithelial cells.
• Phenotypic analysis using video-microscopy and shRNA-mediated gene silencing in human cells.

Main Results:

• A novel mutation in CCDC65 was identified in a PCD patient, leading to a premature termination codon.
• CCDC65, a component of the nexin-dynein regulatory complex, was localized to cilia in normal cells but absent in the patient's cells.
• Patient-derived cells and CCDC65-silenced cells exhibited dyskinetic cilia beating patterns and absence of Gas8, another regulatory complex component.

Conclusions:

• Mutation in CCDC65, a nexin-dynein regulatory complex member, causes PCD with altered cilia motility.
• This study demonstrates PCD can occur without detectable ciliary axoneme ultrastructural defects.
• The findings underscore the significance of the nexin-dynein regulatory complex and suggest limitations in current diagnostic approaches for PCD.