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Wistar Scientists Link Mutation to a Severe Lung Disease

April 14, 2022

Newly published research identifies a mutation associated with scarring of the lungs, revealing a useful diagnostic tool and target for gene therapy.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease that can cause death within five years of diagnosis. In an international research collaboration recently published in the Journal of Experimental Medicine, Wistar scientists and colleagues in the Netherlands identified a mutation on telomeres – which protect the ends of chromosomes – that helps explain this disease. This study directly links the telomeric protein POT1 (Protection of Telomeres Protein 1) to IPF.

Emmanuel Skordalakes, Ph.D., Associate Professor in the Gene Expression and Regulation Program at Wistar and senior author of the paper, previously published research in Nature Communications that delved into the structure and function of POT1, the protein that binds the ends of our chromosomes (telomeres) and protects them from DNA damage response (DDR).

In this new study, Skordalakes and his team used patient data obtained by their Dutch counterparts and conducted a series of biophysical and biochemical experiments to understand how telomeres with mutated POT1 are linked to IPF. Proteins usually have particular sites, which allows them to bind to molecules that match that specific pocket. The team observed that in this chronic lung disease, the mutated POT1 affected how the protein binds to the telomere and thus its ability to prevent DDR.

“We found the mutated POT1 does not bind the telomere as efficiently as the wild type one,” said Skordalakes. The less effective binding of POT1 leaves telomeres exposed to DDR. When this occurs, cells undergo a process called senescence that stops them from functioning and dividing.

“We looked at the [cells of] these patients and they are senescent,” Skordalakes shares. Senescent lung cells build up and contribute to many symptoms of IPF like difficulty in breathing.

The POT1 mutation will be added to a medical database to be used in hospitals to help diagnose patients with IPF as well as provide doctors a target for gene therapy. Skordalakes says, “When you know that your work has an impact on patients directly in the clinic – that’s what’s exciting.”