Pulmonary Fibrosis in Woman Traced to a Rare Gene Mutation Unrelated to Telomere Shortening

A case report of a woman with pulmonary fibrosis and a rare telomere mutation raised the possibility that telomere-associated fibrosis can be observed without shortened telomeres. The study, “TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis“, published in the journal Case Reports in Pulmonology, proposed that the TINF2 gene might be a cause of pulmonary fibrosis.

Telomeres are the DNA sequences capping the ends of the chromosomes, protecting them from wear and tear, as well as from fusion with another chromosome. These sequences shorten as we age, but various genetic mutations can also lead to an abnormal shortening of telomeres, with deleterious consequences like lung fibrosis.

Telomere gene mutations are linked to 25 percent of familial and 3 percent of sporadic pulmonary fibrosis cases. Recently, the TINF2 gene identified in familial pulmonary fibrosis was added to a list of previously known fibrosis-associated telomere genes.

While sequencing genes of 158 pulmonary fibrosis patients, researchers found a TINF2 mutation in a 52-year-old woman who had, up to that time point, been healthy. She was diagnosed with pulmonary fibrosis at 52, and died of her disease six years later.

The particular mutation, called Ser245Tyr, had been described in only five individuals previously, none of whom had pulmonary fibrosis, and two of whom were asymptomatic.

Researchers at St. Antonius Hospital, the Netherlands, retrospectively analyzed the woman’s case and observed that, like other patients with this particular mutation, she did not have shortened telomeres, a finding that worked against such a mutation having contributed to her lung fibrosis.

Most mutations affecting telomere length can be found in a cluster associated with telomere shortening. The Ser245Tyr mutation is found outside of this cluster, leading some researchers to conclude that it does not cause telomere syndrome. Others, however, do not agree — noting that mice without the gene in their lung alveoli develop pulmonary fibrosis. Computer-based analyses of this mutation also suggests that it should be damaging.

Based on these facts, the authors argued that the mutation likely affects the function, but not the length, of the telomeres. Therefore, short telomeres are not necessarily a prerequisite for telomere syndrome, including conditions like pulmonary fibrosis.