Mechanisms of telomerase RNA insufficiency in familial pulmonary fibrosis

Johns Hopkins University, Baltimore MD

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Abstract

PROJECT SUMMARY/ABSTRACT Lung disease is the third leading cause of death in the United States and pulmonary fibrosis is a major culprit. In approximately 20% of cases pulmonary fibrosis is familial, yet, in most of these the genetic etiology is unknown. In at least half of these patients, abnormally short telomeres are a contributing risk factor. Telomeres are the protein-DNA structures at the ends of the chromosomes that are essential for genome integrity. Telomerase is required for telomere synthesis and insufficiency of its essential component, the telomerase RNA (TR), causes telomere shortening and autosomal dominant pulmonary fibrosis. Intriguingly, while pulmonary fibrosis patients with low TR levels may carry mutations in TR, three other regulators of TR have also been implicated as causes of TR insufficiency in pulmonary fibrosis. However, mutations in these four genes only explain half of the familial pulmonary fibrosis cases with low TR, suggesting that other causal genes are yet to be discovered in the remaining families. Our first aim is to identify novel genetic causes of TR insufficiency in these remaining `low TR' families. To identify these mutations we will use exome sequencing and complementary family genetic analysis. Our second aim is to test if genes involved in RNA regulation are haploinsufficient for TR levels when they are mutated in cells. To do so, we will perform a genetic screen in human cells using CRISPR/Cas9 editing. The proposed studies will advance our understanding of the fundamental aspects of TR regulation in patients with lung disease, while shedding light on fundamentals of telomerase biology.