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NAF1 Loss-of-Function Mutations Linked to Short Telomere Syndrome

NEW YORK (GenomeWeb) – A team led by researchers at Johns Hopkins University has found that mutations in the NAF1 gene appear to increase the risk of emphysema and pulmonary fibrosis (PF) in a small number of adults. These findings add NAF1 to a handful of genes — including TERT, TR, DKC1, TINF2, RTEL1, and PARN — whose mutations increase the risk of developing certain disorders linked to shortened telomeres.

"Lung disease is the third leading cause of death in the United States," the researchers wrote, adding that chronic obstructive pulmonary disease — which includes emphysema and PF — is a major contributor to higher risk of death. While other studies have noted that both emphysema and pulmonary fibrosis cluster in families, the underlying genetic mechanism is not understood.

Patients with lung disease caused by short telomeres can be especially sensitive to medications, especially immune-suppressing drugs used during lung transplants. These patients "need to be identified through molecular testing and treated with special care," Mary Armenios, an associate oncology professor at Johns Hopkins and corresponding author, said in a statement. "It's very clear now that making the short telomere syndrome diagnosis prior to transplant is essential to managing these patients."

As they reported today in Science Translational Medicine, the researchers initially collected blood samples from five patients who they identified as having unusually short telomeres using flow-FISH, and sequenced their whole genomes on the Illumina HiSeq 2000 platform.

The team's search identified a mutation in NAF1, a protein coding gene necessary for ensuring the stability of telomerase RNA, in one PF-emphysema patient and in the patient's family members. The researchers went on to sequence the whole genomes of 25 other PF patients and discovered another mutation in NAF1 in a woman who also had bone marrow failure.

Both mutations were linked to lower levels of telomerase RNA. The researchers also found 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 their suspicions about the impact of NAF1 mutations on telomerase, the researchers generated NAF1-null mice using CRISPR/Cas9 and then genotyped them. They found that the mutations decreased telomerase RNA by half in the mice but did not affect the function of other RNAs in the body.

"What that told us is that even the loss of one copy of NAF1 results in loss of telomerase, and this is enough to disturb the whole system," Armenios said. "Despite that, the functions of these other RNAs were preserved, while the loss of telomerase RNA caused telomere shortening."

In their paper, Armenios and her colleagues wrote that future research efforts should focus on efforts to either reverse the telomere defect or find regenerative approaches to find the best therapies for PF-emphysema patients with shorter telomeres.

"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," she added.

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