Telomerase and idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of telomere-mediated disorders. Germline mutations in the essential telomerase genes, hTERT and hTR, are the causal genetic defect in up to one-sixth of pulmonary fibrosis families. The presence of telomerase mutations in this subset is significant for clinical decisions as affected individuals can develop extra-pulmonary complications related to telomere shortening such as bone marrow failure and cryptogenic liver cirrhosis. There is also evidence that IPF is an ancestral manifestation of autosomal dominant telomere syndromes where, with successive generations, the disease evolves from pulmonary fibrosis into a bone marrow failure-predominant disorder, defining a unique form of genetic anticipation. Here I review the significance of telomere defects for understanding the genetics, disease patterns and pathophysiology of IPF. The importance of this diagnosis for patient care decisions will also be discussed.

Figure 1. Pulmonary fibrosis is a progressive disease

Serial computed tomography (CT) lung images over a seven year period from an individual with a germline mutation in hTERT, the gene for the telomerase reverse transcriptase. Her age at the time of imaging is noted above the images which show progressive reticular infiltrates with honeycombing changes in the basilar and peripheral portions of the lung. The patient died from end stage lung disease at the age of 61.

Figure 2. Mutant telomerase genes cause telomere shortening by haploinsufficiency

In left panel, wildtype telomerase maintains telomeres, but in the presence of heterozygous hTERT and hTR mutations, haploinsufficiency causes telomere shortening.

Figure 3. Autosomal dominant telomere syndromes show a unique pattern of genetic anticipation

Example schema of a pedigree with a mutant hTR or hTERT gene shows consecutive generations affected. In addition to the mutant allele (blue), short telomeres are also inherited and telomerase haploinsufficiency causes successive telomere shortening as shown by the decreasing length (red). Concurrently the disease severity worsens as illustrated by the darker shades of black. Unique to autosomal dominant telomere syndromes, the phenotype pattern evolves from idiopathic pulmonary fibrosis (IPF) to a bone marrow failure-predominant disorder manifesting as aplastic anemia (AA), or even possibly the full spectrum of dyskeratosis congenita (DC). The number of generations across which this evolving pattern may be appreciated can be longer than three generations.