Posts by: Vanessa Pataia

Mutations in a protein-coding gene called NEK10 can affect the structure and function of cilia — small eyelash-like projections that help move mucus through the airways — compromising mucus clearance from the lungs and leading to the onset of bronchiectasis, a study has found. Titled “A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance,” the study was published in the journal Nature Medicine. Mucus builds up in the lung airways in bronchiectasis due to a problem with mucociliary clearance, which is the process by which cilia in the respiratory system move to help eliminate microbes and other harmful substances from the airways. Bronchiectasis can occur sporadically and be triggered by a common childhood infection — measles or whooping cough, for example — or be associated with a genetic condition such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD), or an immunodeficiency. Although some mutations that affect the structure of cilia have been identified in people with PCD, the regulation of mucociliary transport is still not fully understood. Due to this, potential therapeutic candidates are lacking. Now, researchers in the U.S. and Saudi Arabia performed genetic tests in an attempt to identify new mutations affecting mucociliary clearance that could be directly associated with bronchieactasis. The testing was done in several families of individuals who had the disease but were lacking a genetic explanation for their disorder. The technique used by investigators, called whole exome sequencing (WES), examines the DNA sequence (exome) of all genes that provide instructions to make proteins to seek a disease's genetic cause. In the first family, the team found a mutation in one intron — a region of a gene that does not encode a protein — of the NEK10 gene (c.1230+5G>C) that had never been linked to human disease. This gene provides instructions to make the NIMA-related kinase 10, or NEK10 protein, whose functions are still poorly characterized. They also found this particular mutation led to the addition of seven amino acids — the building blocks of proteins — to the protein sequence, making NEK10 highly unstable. “These findings led us to ask whether NEK10 mutations might underlie other cases of unexplained bronchiectasis," the researchers said. "Indeed, further sequencing revealed six additional patients from four families who harbored ... NEK10 mutations and exhibited bronchiectasis,” they said. In two of these families, they found two mutations, specifically c.1869dupT and c.1373+1G>T, that caused an error in the reading frame of the NEK10 gene. A reading frame refers to the specific way nucleotides — the building blocks of DNA — in the gene sequence are grouped and “read” together, providing proper instructions to make a functional protein. That error in the reading frame resulted in the production of a shorter NEK10 protein. In the two other families, investigators found two mutations — c.2243C>T and c.2243C>T — that led to the substitution of one amino acid for another in a region of the NEK10 protein sequence. That substitution is likely to affect its function, the researchers said. To understand how a mutation in NEK10 could be linked to bronchiectasis, the scientists then examined cells collected from the airways of one of the members of the first family in the study. They used the cells to recreate in a lab dish the tissue lining the patient’s airways. Using powerful microscopy and imaging techniques, the investigators found that cilia in the patient's recreated airway tissue were shorter and moved much slowly than that of controls — airway tissue created from cells collected from individuals who did not have bronchiectasis. Based on these observations, the scientists suggested that “this relatively subtle ... abnormality should be more regularly evaluated for patients with otherwise unexplained mucus clearance deficiencies. "It may be more common than is currently appreciated,” they said. No differences were found in the total number of cilia, beat frequency, or radial structure between patient and control airway tissues, the scientists said. Further experiments also suggested NEK10 may have an important role in preventing the destruction of other proteins involved in the formation of cilia, according to the team. This work “opens the door to understanding new regulatory networks in ciliated cells and, based on this understanding, potentially to targeting this signaling axis in more common diseases of mucociliary clearance where promotion of mucociliary transport may be therapeutically beneficial,” the scientists said.

Posts by: Vanessa Pataia

Vanessa Pataia

Smoking, Respiratory Issues, Older Age Raise Hospital Costs, Chinese Study Finds

Mutations in Protein-Coding NEK10 Gene Can Compromise Mucus Clearance and Lead to Bronchiectasis, Study Finds