May 05, 2020
Genetic Disorders of Mucociliary Clearance Consortium

What is the genetic cause behind impaired mucociliary clearance of the lungs? Researchers from the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) contributed to the discovery of a new disease gene, NEK10, that regulates cilia length.

Cilia are hair-like structures that line the airways in the lungs. Their job is to push mucus up through the airways, removing the potentially harmful dirt and pathogens we breathe in. This defense mechanism of the lungs is called mucociliary clearance.

The macro-structure of cilia is important—if they are too short, they are unable to effectively move the mucus through the airways. When the mucus becomes so thick that cilia can’t push it out, this can cause swelling of the bronchi (bronchiectasis).

Previously, not much was known about the genetic causes behind mucociliary clearance and cilia macro-structure. But when researchers discovered a new lung disease associated with a mutation in the NEK10 gene, they identified a novel link to ciliary function. NEK10, they discovered, has an essential function in airway mucociliary clearance—the gene controls ciliary length, number, structure, and beat frequency.

How did researchers discover this new lung disease and, ultimately, the functions of NEK10? Initial clues originated from a 31-year-old patient with a severe respiratory infection. Although the patient had experienced respiratory issues since she was a baby, she tested negative for likely causes such as cystic fibrosis.

Raghu Chivukula, MD, PhD, of Massachusetts General Hospital assembled a team of researchers to solve this mystery. By testing genetic samples from the patient and her family, they discovered one commonality—they all showed mutations in the NEK10 gene. Further analysis of other patients with this mutation illuminated an association between NEK10 and mucociliary clearance. The mutation causes the cilia to be too short, resulting in these previously unexplainable respiratory infections.

The genetic cause behind this new lung disease has potential implications for other respiratory disorders characterized by impaired mucociliary clearance, including cystic fibrosis and primary ciliary dyskinesia (PCD). Now that researchers understand the function of NEK10, they can explore new treatments to target the gene.

The research team recently published their findings in Nature Medicine. GDMCC researchers contributed supporting data, including genetic, clinical phenotype, and ciliary function data. The team includes Maimoona A. Zariwala, PhD; Johnny Carson, PhD; M. Leigh Anne Daniels, MD, MPH; Patrick R. Sears, PhD; Michael R. Knowles, MD; and many others at the University of North Carolina at Chapel Hill who co-authored and contributed to this work.

Read the full story behind the discovery in Medical Xpress.