Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

Abstract

In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.Keywords: aging; alpha-1 antitrypsin deficiency; senescence; idiopathic pulmonary fibrosis; hepatopulmonary syndrome

Long telomeres and cancer risk: the price of cellular immortality

“…A more severe form manifests in infants and children; it causes disease in high-turnover tissues and primarily recognized as immunodeficiency, bone marrow failure, and enteropathy (16,19,20,44). Adultonset short telomere syndromes are more common and account for at least 90% of presentations (45). They manifest most frequently as idiopathic pulmonary fibrosis (IPF) and other telomererelated lung disease (45).…”

“…Adultonset short telomere syndromes are more common and account for at least 90% of presentations (45). They manifest most frequently as idiopathic pulmonary fibrosis (IPF) and other telomererelated lung disease (45). These telomere-related lung disorders in the vast majority show autosomal dominant inheritance and may appear as emphysema in smokers (45,46).…”

“…They manifest most frequently as idiopathic pulmonary fibrosis (IPF) and other telomererelated lung disease (45). These telomere-related lung disorders in the vast majority show autosomal dominant inheritance and may appear as emphysema in smokers (45,46). IPF affects 100,000 individuals in the United States alone, and at least 50% of IPF patients have telomere length in the lowest decile of the population (45).…”

“…These telomere-related lung disorders in the vast majority show autosomal dominant inheritance and may appear as emphysema in smokers (45,46). IPF affects 100,000 individuals in the United States alone, and at least 50% of IPF patients have telomere length in the lowest decile of the population (45). In one-third of families with pulmonary fibrosis, a mutation in telomerase or telomere-related genes is detectable (45).…”

“…IPF affects 100,000 individuals in the United States alone, and at least 50% of IPF patients have telomere length in the lowest decile of the population (45). In one-third of families with pulmonary fibrosis, a mutation in telomerase or telomere-related genes is detectable (45). The high frequency of telomere defects in IPF and the prevalence of this disease make IPF the most common of the human short telomere phenotypes.…”