Newly Found Genetic Mutation Seen to Increase Risk of Pulmonary Fibrosis

Researchers at Johns Hopkins University have identified a new gene that, when mutated, increases the risk for pulmonary fibrosis and emphysema by reducing the activity of telomerase, the enzyme that maintains the protective caps, or telomeres, on chromosomes.

The study, “Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis–emphysema,” published in Science Translational Medicine, adds the new gene — NAF1 — to the list of genes involved in certain disorders associated with shortened telomeres.

Telomeres are protective coverings on the tips of chromosomes that prevent their ends from unraveling, similar to the plastic cap at the end of a shoelace. Although our telomeres become shorter as we age, telomerase works to prevent the rapid shortening of telomeres. This is important because once the chromosomes loose their telomeres, the cells stop dividing — or worse, they start acquiring mutations and may turn into malignant cells.

Mutations in the telomerase gene or in other genes that affect how well telomerase works may lead to abnormally short telomeres. This is associated with a condition called short telomere syndrome that manifests as pulmonary fibrosis or emphysema. Patients are also at risk for leukemia, bone marrow failure, and liver disease.

Researchers examined the genome of patients with short telomere syndrome to identify new genes linked with the disease. As they did not find any new mutations, they looked for genes that reduced the telomerase RNA, which is critical for telomerase activity. In one of the patients, the investigators identified a mutation in the NAF1 gene, which generates a protein that maintains the stability of the telomerase RNA.

They then analyzed the genome of 25 patients with pulmonary fibrosis, and a woman who had both pulmonary fibrosis and bone marrow failure was found to have a mutation in the NAF1 gene. In both patients with NAF1 mutations, the mutations impaired the NAF1 protein from entering the nucleus and stabilizing telomerase RNA.

In mice, researchers found that the NAF1 mutation decreased the levels of telomerase RNA by half, which was enough to decrease the telomere’s length. But it did not affect the levels of other RNA molecules, which was surprising since NAF1 is involved in the stabilization of 100 different RNAs.

The authors believe that identifying these mutations in pulmonary fibrosis patients is important, because patients with decreased telomerase activity are more susceptible to certain therapies, especially immunosuppressants, which are given during bone marrow or lung transplants.

“It’s very clear now that making the short telomere syndrome diagnosis prior to transplant is essential to managing these patients,” Dr. Mary Armanios, MD, an associate professor of oncology at Johns Hopkins University School of Medicine, said in a press release.

The study also “suggests that telomere defects may be more common than expected in patients with pulmonary fibrosis-emphysema, and it sheds further light on the root cause of these devastating conditions with the hope of identifying new therapies,” Armanios added.