HMN 2025: How genetic mutations cause pulmonary fibrosis

A research group from the National Cancer Research Center (CNIO) has found that an alteration in the POT1 gene prevents lung tissue from regenerating, which over time makes breathing difficult. The mutation prevents telomeres, the structures that protect chromosomes, from repairing. According to the authors, understanding the effect of mutations like this is critical to developing personalized therapies against telomere syndromes, a group of diseases that includes pulmonary fibrosis and several cancer types.

Idiopathic pulmonary fibrosis is a potentially fatal disease currently without treatment, in which lung tissue develops scarring and becomes stiff, making breathing increasingly difficult over time. The process is not yet well understood at the molecular scale and is being actively researched.

We know that pulmonary fibrosis is strongly linked to dysfunctional telomeres, the structures that protect chromosomes. This finding was discovered a few years ago by the Telomeres and Telomerase Group—Humanism and Science Foundation at the National Cancer Research Center (CNIO), opening up new avenues to develop therapies against the disease.

The same group, led by Maria Blasco, is now making even more headway, revealing the mechanism by which a certain genetic mutation results in pulmonary fibrosis.

As explained in the journal Genes and Development, an in-depth understanding of the effect of mutations such as the one studied “is essential to develop personalized therapies” against so-called telomere syndromes, a group of around a dozen diseases, including pulmonary fibrosis and many types of cancer.

A mutation that prevents telomeres from repairing

The current study focuses on a mutation in the POT1 gene, which produces one of the proteins called shelterins that make up the protective shield of telomeres. The CNIO research group has discovered that, when this mutation is present, telomeres cannot be repaired, because the enzyme responsible for such repairs is unable to operate normally.

“We have shown that this mutation stops telomerase from working in the telomere,” explains Blasco, lead author in this study, which also involved Paula Martínez and Raúl Sánchez-Vázquez, from the same research group.

“The study helps explain why people with this mutation have short telomeres and develop pulmonary fibrosis, just like people with telomerase mutations. These findings emphasize the prevalence of short and dysfunctional telomeres in the development of pulmonary fibrosis in humans,” Blasco adds.

Altered ‘shelterins,’ unprotected telomeres

Telomeres are molecular structures found at the ends of chromosomes, acting as protective caps for chromosome integrity. Throughout life telomeres become naturally shorter—an unavoidable consequence of cell division—and, if they become too short, cells stop dividing. This means that the tissue does not regenerate. In lung tissue, non-regeneration due to telomere dysfunction causes fibrosis.

This was proved in previous studies by Blasco’s group, who also discovered that it is possible to reverse fibrosis in animals by activating the telomerase enzyme in affected tissues.

However, in the current study they note that when the POT1 shelterin protein mutates, telomeres are impossible to repair, even when telomerase is present. Fibrosis appears as a result.

“We see that this mutation in POT1 is identical to the mutation in telomerase,” Blasco explains. “This is the first time a mutation has been found in a shelterin protein that has the same effect as lacking telomerase.”

POT1 in cancer and aging

So far, all POT1 mutations had been associated with cancer, and in fact, Blasco’s group has broken new ground in characterizing the role of POT1 mutations in cancer. The POT1 mutation studied in the current research is the first to be associated with a degenerative disease such as pulmonary fibrosis.

“The fact that the same telomere protein, POT1, can lead to cancer or aging demonstrates the essential role of telomeres in these diseases,” says the head of the CNIO Telomere and Telomerase Group—Humanism and Science Foundation.

The CNIO spin-off company Telomere Therapeutics created a few years ago is currently developing therapies based on the activation of the enzyme telomerase in affected tissues. The now published study, however, shows the importance of personalizing treatments, since telomerase activation would not solve the problem in fibrosis caused by POT1 mutations.

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