Genetic and environmental factors influencing human diseases with telomere dysfunction

Abstract

Both genetic and environmental factors have been implicated in the mechanism underlying the pathogenesis of serious and fatal forms of human blood disorder (acquired aplastic anemia, AA) and lung disease (idiopathic pulmonary fibrosis, IPF). We and other researchers have recently shown that naturally occurring mutations in genes encoding the telomere maintenance complex (telomerase) may predispose patients to the development of AA or IPF. Epidemiological data have shown that environmental factors can also cause and/or exacerbate the pathogenesis of these diseases. The exact mechanisms that these germ-line mutations in telomere maintenance genes coupled with environmental insults lead to ineffective hematopoiesis in AA and lung scarring in IPF are not well understood, however. In this article, we provide a summary of evidence for environmental and genetic factors influencing the diseases. These studies provide important insights into the interplay between environmental and genetic factors leading to human diseases with telomere dysfunction.

Keywords: Telomeres; aplastic anemia; dyskeratosis congenita; environmental factors; idiopathic pulmonary fibrosis; telomerase.

Figure 1

Linear chromosome end consists of the double stranded DNA sequence and the single-strand DNA (ssDNA) of repeated sequence (TTAGGG)n. The T-loop structure is formed by a strand-invasion event of the terminal 3′ ssDNA into the double stranded telomeric sequence, and is composed of telomere associated with the teiomere-binding protein factors of the sheiterin complex.

Figure 2

(A) Schematic diagram of the telomerase RNP complex. Template sequence of TER (or TERC) RNA (nts 46-53) and other conserved structural domains (CR4-CR5, pseudoknot, and Box H/ACA) are indicated. The representative DC-associated TER variants are shown in black, AA-associated mutations in red, and IPF mutations in blue. Rare SNPs (G58A and G228A) that have been found in both patients and healthy controls are shown in white. The TER-associated proteins Dyskerin, NHP2, NOP10 and GAR1 are also shown. (B) A linear depiction of human TERT protein with some of its known natural sequence variations is shown. IPF-associated mutations are shown in blue, DC-associated mutations in black, AA-associated mutations in red, and rare SNPs in gray. RT: reverse transcriptase domain.

Figure 3

A proposed scheme of how genetic and environmental factors may work in concert to cause human diseases with telomere dysfunction. While disease-associated mutations in some components of telomerase (e.g., hTER, hTERT) can directly cause telomere dysfunction, the effect may also be caused or exacerbated by oxidative stress mediated through a cellular response to environmental factors (e.g., benzene or cigarette smoke) and/or by other yet unknown cellular gene products. Critically short or damaged telomeres can force cells into an arrested state (senescence) or to die (apoptosis) that can result in defect in tissue reserve, renewal and repair capacities. These effects collectively may lead to the clinical disease of AA and IPF.