Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies

Abstract

Premature loss of telomere repeats underlies the pathologies of inherited bone marrow failure syndromes. Over the past decade, researchers have mapped genetic lesions responsible for the accelerated loss of telomere repeats. Haploinsufficiencies in the catalytic core components of the telomere maintenance enzyme telomerase, as well as genetic defects in telomerase holoenzyme components responsible for enzyme stability, have been linked to hematopoietic failure pathologies. Frequencies of these disease-associated alleles in human populations are low. Accordingly, the diseases themselves are rare. On the other hand, single nucleotide polymorphisms of telomerase enzyme components are found with much higher frequencies, with several non-synonymous SNP alleles observed in 2-4% of the general population. Importantly, recent advents of molecular diagnostic techniques have uncovered links between telomere length maintenance deficiencies and an increasing number of pathologies unrelated to the hematopoietic system. In these cases, short telomere length correlates to tissue renewal capacities and predicts clinical progression and disease severity. To the authors of this review, these new discoveries imply that even minor genetic defects in telomere maintenance can culminate in the premature failure of tissue compartments with high renewal rates. In this review, we discuss the biology and molecules of telomere maintenance, and the pathologies associated with an accelerated loss of telomeres, along with their etiologies. We also discuss single nucleotide polymorphisms of key telomerase components and their association with tissue renewal deficiency syndromes and other pathologies. We suggest that inter-individual variability in telomere maintenance capacity could play a significant role in chronic inflammatory diseases, and that this is not yet fully appreciated in the translational research of pharmacogenomics and personalized medicine.

Many disease-associated variants of hTERT retain high telomerase enzymatic activity

“…Frequency = 0, allele found in a family described in the literature but not in the Exome Sequencing Project.RRL activity, HEK activity and VA13 activity, direct assay results from this study.Published activity, references given in the same order as the activity values.RRL processivity determined by the linear regression method, and HEK processivity determined by the >15 repeats method, all from this study.Disease: IPF, idiopathic pulmonary fibrosis; AML, acute myloid leukemia; AA, aplastic anemia; DC, dyskeratosis congenita. a These alleles were originally reported as disease-associated, but the disease association is now thought to be modest [discussed in (14)].…”

“…The rare inherited disorder dyskeratosis congenita (characterized by defects in highly proliferative tissues such as skin and bone marrow) has been traced to insufficient telomerase activity due to mutations in the dyskerin protein subunit (8), the telomerase RNA (9) and TERT (10), or in telomere components such as TINF2 and RTEL1 (11–13). Recently, other diseases including idiopathic pulmonary fibrosis and aplastic anemia have been associated with telomerase deficiency (14). Telomerase deficiency also contributes to multiple forms of cancer, presumably because short telomeres lead to genome instability which contributes to oncogenesis (15–18).…”

“…Heterozygotes with one defective allele of hTERT or hTR are unable to maintain highly proliferative tissues because of haploinsufficiency (10,14,19). Interestingly, a related situation occurs in yeast, where telomerase RNA is haploinsufficient for telomere length maintenance (20).…”

Association between Genetic Variations Affecting Mean Telomere Length and the Prevalence of Hypertension and Coronary Heart Disease in Koreans

“…In addition, rs398652 genetic variants have an obvious impact on TL and esophageal squamous cell carcinoma susceptibility in Chinese populations [14]. While evidence for the causal role of TL variation in some chronic diseases has accumulated [15], the link between SNPs involved in telomere biology and the risk of hypertension (HTN), CHD, and its risk factors, has not been extensively studied in Korean populations. In this study, we examined whether SNPs previously reported to be associated with TL in humans are related to the incidence of HTN/CHD and risk factors of CVD, in a Korean population.…”

Altering Fate Determination of Human Bone Marrow-Derived Mesenchymal Stem Cells through Environmental and Transcriptional Cues

“…75 Despite this finding, there does appear to be an association between ex vivo cell senescence and organismal lifespan, and studies of telomerase mutations in humans have revealed an association with diseases of aging in which tissue compartments require a high degree of cell self-renewal. 76 Similarly, short telomeres have been linked with some tissue-specific degenerative diseases, and telomere length is evaluated as a clinical parameter in determining therapeutic approaches. 77 Ablation of senescent cells in progeroid mice has been shown to delay or rescue the aging phenotype at the organismal level, implicating senescent cells in the pathogenesis of age-related disease in vivo.…”