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Identification of Novel Bronchiectasis Syndrome Has Implications for Other Respiratory Diseases

Key findings

  • Researchers at Massachusetts General Hospital have described a novel bronchiectasis syndrome caused by NEK10 deficiency and characterized by pathologically short cilia
  • NEK10 was found to control mucociliary clearance
  • Individuals with NEK10 mutations had undergone standard evaluation for primary ciliary dyskinesia, which failed to detect ciliary shortening
  • NEK10 signaling may prove to be a therapeutic target in more common diseases of mucociliary clearance

By looking for the genetic cause of bronchiectasis in a single family, Raghu Chivukula, MD, PhD, a physician-scientist in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, David M. Sabatini, MD, PhD, member at the Whitehead Institute for Biomedical Research and professor of Biology at the Massachusetts Institute of Technology, and colleagues discovered a novel signaling axis that controls mucociliary clearance that has implications for the treatment of other respiratory disorders. Their findings were published in Nature Medicine.

The Discovery

A 31-year-old woman, the daughter of a consanguineous couple, was evaluated for recurrent bacterial sinopulmonary infections. Chest imaging demonstrated extensive bronchiectasis. Cystic fibrosis and immunodeficiency were ruled out and her nasal cilia appeared structurally normal on biopsy.

Two siblings of the patient had similar, milder findings, and all three underwent whole-exome sequencing. This unexpectedly revealed homozygous mutations in NEK10, which had not been implicated previously in human disease. The mutation proved to lead to the addition of seven amino acids to the NEK10 protein sequence, rendering NEK10 highly unstable and causing loss of function.

Other Cases

Suspecting that mutated NEK10 might underlie other cases of unexplained bronchiectasis, the researchers performed further sequencing. They detected homozygous NEK10 mutations in six individuals from four families.

Clinical testing of these six patients revealed normal ciliary structure on electron microscopy and only very subtle abnormalities on video microscopy. This suggests patients with NEK10-related ciliary shortening might escape detection during standard evaluation for primary ciliary dyskinesia.

Basic Research

Cultures of airway epithelium with mutated NEK10 showed nearly absent mucociliary transport but a normal ciliary beat frequency. Using CRISPR–Cas9 genome editing, the research team removed NEK10 from healthy cells and found that cilia moved abnormally because they were too short. Further experimentation showed that potentiation of NEK10 activity might augment mucociliary transport.

Clinical Relevance

Ciliary shortening may be more common than currently appreciated. Standard algorithms for ruling out primary ciliary dyskinesia may fail to capture patients who have ciliary shortening and impaired mucociliary transport. Patients who have otherwise unexplained mucus clearance deficiencies should be regularly evaluated for ciliary shortening.

This report is the first to directly implicate a kinase mutation in ciliary dyskinesia, so it also suggests a new direction for research into regulatory networks in ciliated cells. NEK10 signaling may prove to be a therapeutic target in more common diseases of mucociliary clearance where the promotion of mucociliary transport would be beneficial.

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