Telomere Dysfunction in Human Genetic Disease


Telomeres are specialised deoxyribonucleic acid (DNA) structures that cap the ends of chromosomes to protect genomic DNA. Telomerase is the enzyme that regulates telomere length to maintain the protective functions of telomeres. A major risk factor for some human diseases is telomere and telomerase dysfunction. Bone marrow deficiency syndromes as well as diabetes, hypertension and atherosclerosis have all been linked to alterations to telomeres or mutations in telomerase genes. The precise biological mechanisms involved in most of the diseases, however, are poorly understood. Research aimed at describing the biological processes that underlie these pathologies may elucidate the precise roles that telomeres and telomerase play in the progression of these diseases. Markers of telomere dynamics, such as telomere length and screening for telomerase mutations, may have some prognostic value related to these disorders.

Key Concepts:

  • Telomeres are repeats of the nucleic acid sequence TTAGGG.

  • T‐loop structure is composed of telomeric DNA and shelterin proteins.

  • Telomeres help maintain genomic stability in the cell.

  • Progressive telomeric repeat loss occurs due to the end‐replication problem and genotoxic stress.

  • Telomerase in an enzyme that adds TTAGGG repeats to 3′ ends of telomeres.

  • Bone‐marrow failure syndromes, such as dyskeratosis congenita, aplastic anaemia and idiopathic pulmonary fibrosis have been linked to telomere and telomerase dysfunctions.

  • Chronic diseases such as cardiovascular disease and diabetes have also been linked to telomere alterations.

  • In vitro and in vivo research may demonstrate the precise role telomeres play in these disease processes.

  • In vivo studies may lead to development of diagnostic markers and therapies for these diseases.

Keywords: telomeres; telomerase; bone‐marrow failure syndromes; dyskeratosis congenita; aplastic anaemia; idiopathic pulmonary fibrosis

Figure 1.

Simplified illustration of the telomerase holoenzyme showing its main components: hTERT, hTERC, Dyskerin, NOP10, NHP2, GAR1 and TCAB1. Functional regions of the hTERC RNA (template, pseudoknot, CR4‐CR5, Box H/ACA and CR7) are indicated. Reproduced from Carroll and Ly , with permission from e‐Century Publishing Corporation.

Figure 2.

Shelterin complex: (a) Six components of the telomere‐binding complex, shelterin and their DNA and protein‐binding abilities. (b) A schematic of the shelterin complex bound to the telomere T‐loop structure. (c) A proposed model for how shelterin can function to control telomere length in cis. Long telomeres allow for more shelterin binding, which can block access of telomerase to the telomere end. In contrast, a short telomere with less shelterin bound is preferentially elongated by telomerase. Reproduced from Carroll and Ly , with permission from e‐Century Publishing Corporation.

Figure 3.

Representative mutations in (a) hTERT, (b) hTERC and (c) TIN2 identified in patients and/or controls are shown. Mutations are colour‐coded according to the disease in which they were first identified. Those denoted with an asterisk (*) have been found in multiple telomere dysfunction disorders (H412Y: AA, AML; V694M: AA, IPF; P704S: DC, IPF, A37G: DC, IPF; Δ110–113: AA, MDS; C116T: AA, MDS, R282C: DC, AA; R282H: DC, AA; F290LfsX2: DC, AA). AA, aplastic anaemia; DC, dyskeratosis congenita; IPF, idiopathic pulmonary fibrosis; AML, acute myeloid leukaemia. Acidic and basic domains in the TIN2 protein are denoted based on the amino acid content in these regions. The TRFH domain is the general region that has been shown to interact with TRF1. Reproduced from Carroll and Ly , with permission from e‐Century Publishing Corporation.



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Further Reading

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Marx J (2002) Chromosome end game draws a crowd. Science 295: 2348–2351.

Zakian VA (2011) The ends have arrived. Cell 139: 1038–1040.

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Morgan, Garrett, and Ly, Hinh(Oct 2011) Telomere Dysfunction in Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023585]