Researchers at Johns Hopkins Medicine have identified a new disease gene that, when mutated, appears to increase the risk in a small number of people of developing emphysema and pulmonary fibrosis.
According to Science Daily, NAF1, the affected gene, joins a handful of genes in which mutations increase the risk of certain disorders linked to malfunctioning shortened telomeres. The researchers indicate that about 2% to 4% of cases of pulmonary fibrosis-emphysema without other known causes may be due to mutations in NAF1.
For the study, the researchers, looking for new diseased genes, sequenced the whole genomes of five people who had abnormally short telomeres and signs of short telomere syndrome. The approach did not turn up new mutations, so the research team subsequently examined the group to see which individuals had unusually low levels of telomerase RNA and started a new search for mutations in the genes that produce it. This search did turn up a mutation in NAF1 in a pulmonary fibrosis-emphysema patient the team evaluated, and other family members also carried the mutation.
The researchers went on to sequence the genomes of 25 other pulmonary fibrosis patients, finding a second NAF1 mutation in a woman who also had bone marrow failure. These two mutations were linked to lower levels of telomerase RNA. The Science Daily news report indicates that the mutant NAF1 protein in these patients was defective: It was missing a component that permits its entry into the nucleus where it stabilizes telomerase RNA.
To confirm the assumed impact of the NAF1 mutations on telomerase, the researchers used the gene editing technique CRISPR/Cas9 to include a mutation in the NAF1 gene of mice. The team discovered that the mutations decreased levels of telomerase RNA by half in the mice, but did not affect the function of other RNAs in the body.
Mary Armanios, MD, says, “What that told us is that even the loss of one copy of NAF1 results in loss of telomerase, and that is enough to disturb the whole system. Despite that the functions of these other RNAs were preserved, while the loss of telomerase RNA caused telomere shortening.”
Telomere shortening may increase the risk of lung disease in these patients by preventing stem cells from diving and replacing injured cells in the lungs, which makes it more difficult for lungs cells to replenish themselves when they are threatened by environmental toxins such as cigarette smoke. “”This study 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 says.
Photo Credit: Mary Armanios, Johns Hopkins Medicine
Source: Science Daily