Telomerase Mutations in Families with Idiopathic Pulmonary Fibrosis

TLDR

Idiopathic pulmonary fibrosis is progressive and often fatal, and the causes of its familial clustering remain unknown. The authors screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for germ‑line hTERT and hTR mutations, identifying heterozygous variants in 8% that caused short telomeres. Mutations in telomerase genes were found in 8% of probands, and asymptomatic carriers also had short telomeres without classic dyskeratosis features, supporting telomere shortening as a pathogenic pathway in familial idiopathic pulmonary fibrosis.

Abstract

Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis.To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR.Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families.Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease.