Pot1 Gene Mutation Linked To Pulmonary Fibrosis Through Telomere Dysfunction

Idiopathic pulmonary fibrosis is simply a perchance fatal illness presently without treatment, successful which lung insubstantial develops scarring and becomes stiff, making breathing progressively difficult complete time. The process is not yet good understood astatine nan molecular standard and is being actively researched.

We cognize that pulmonary fibrosis is powerfully linked to dysfunctional telomeres, nan structures that protect chromosomes. This uncovering was discovered a fewer years agone by nan Telomeres and Telomerase Group – Humanism and Science Foundation at nan National Cancer Research Centre (CNIO), opening up caller avenues to create therapies against nan disease.

The aforesaid group, led by Maria Blasco, is now making moreover much headway, revealing nan system by which a definite genetic mutation results successful pulmonary fibrosis.

As explained successful nan diary Genes and Development, an in-depth knowing of nan effect of mutations specified arsenic nan 1 studied "is basal to create personalized therapies" against alleged telomere syndromes, a group of astir a twelve diseases, including pulmonary fibrosis and galore types of cancer.

A mutation that prevents telomeres from repairing

The existent study focuses connected a mutation successful nan POT1 gene, which produces 1 of nan proteins called shelterins that dress up nan protective shield of telomeres. The CNIO investigation group has discovered that, erstwhile this mutation is present, telomeres cannot beryllium repaired, because nan enzyme responsible for specified repairs is incapable to run normally.

"We person shown that this mutation stops telomerase from moving successful nan telomere," explains Blasco, lead writer successful this study, which besides progressive Paula Martínez and Raúl Sánchez-Vázquez, from nan aforesaid investigation group.

The study helps explicate why group pinch this mutation person short telomeres and create pulmonary fibrosis, conscionable for illustration group pinch telomerase mutations. These findings emphasise nan prevalence of short and dysfunctional telomeres successful nan improvement of pulmonary fibrosis successful humans."

Maria Blasco, lead author

Altered 'shelterins', unprotected telomeres

Telomeres are molecular structures recovered astatine nan ends of chromosomes, acting arsenic protective caps for chromosome integrity. Throughout life telomeres go people shorter - an unavoidable consequence of compartment section – and, if they go excessively short, cells extremity dividing. This intends that nan insubstantial does not regenerate. In lung tissue, non-regeneration owed to telomere dysfunction causes fibrosis.

This was proved successful erstwhile studies by Blasco's group, who besides discovered that it is imaginable to reverse fibrosis successful animals by activating nan telomerase enzyme successful affected tissues.

However, successful nan existent study they statement that erstwhile nan POT1 shelterin macromolecule mutates, telomeres are intolerable to repair, moreover erstwhile telomerase is present. Fibrosis appears arsenic a result.

"We spot that this mutation successful POT1 is identical to nan mutation successful telomerase," Blasco explains. "This is nan first clip a mutation has been recovered successful a shelterin macromolecule that has nan aforesaid effect arsenic lacking telomerase."

POT1 successful crab and aging

So far, each POT1 mutations had been associated pinch cancer, and successful fact, Blasco's group has surgery caller crushed successful characterising nan domiciled of POT1 mutations successful cancer. The POT1 mutation studied successful nan existent investigation is nan first to beryllium associated pinch a degenerative illness specified arsenic pulmonary fibrosis. 

"The truth that nan aforesaid telomere protein, POT1, tin lead to crab aliases ageing demonstrates nan basal domiciled of telomeres successful these diseases," says nan caput of nan CNIO Telomere and Telomerase Group – Humanism and Science Foundation.

Therapeutic strategies

The CNIO rotation disconnected institution Telomere Therapeutics, created a fewer years ago, is presently processing therapies based connected nan activation of nan enzyme telomerase successful affected tissues. The now published study, however, shows nan value of personalising treatments, since telomerase activation would not lick nan problem successful fibrosis caused by POT1 mutations.

European task SHELTERINS

Blasco's group carried retired this study pinch backing from nan SHELTERINS task of nan European Research Council.

The purpose of this project, led by Maria Blasco, is to summation a amended knowing of nan domiciled of shelterin proteins successful cancer, successful bid to look for therapeutic strategies that neutralise tumors expertise to infinitely disagreement by disrupting nan protection of telomeres, which would artifact nan imaginable uncontrolled maturation of tumors.

Within this project, nan group has studied respective mutations successful POT1, which is mutated successful galore types of tumors.