Role of Telomere Length and Telomerase in Human Disease

Short telomeres are characteristic of human diseases of various origins that are associated with ageing, such as cardiovascular disease (Oh et al. 2003, O'Sullivan et al. 2002, Wiemann et al. 2002, Samani et al. 2001). In addition, a correlation between telomere length and risk of death from heart disease or infections has been recently observed (Cawthon et al. 2003), further indicating that telomere length may directly contribute to such diseases. Finally, factors considered to accelerate ageing and to be a risk for premature death, such as perceived stress or obesity, can also negatively impact on telomerase activity levels and telomere length in affected individuals (Epel et al. 2004, Valdes et al. 2005).

In addition, several human premature ageing syndromes are characterized by a faster rate of telomere attrition with age, such as Dyskeratosis congenita (DC; see Du et al., this volume). DC patients carry mutations in components of the telomerase complex which result in decreased telomerase stability and shorter telomeres (Mitchell et al. 1999). These mutations affect either the Terc gene (patients with the autosomal-dominant DC variant) (Vulliamy et al. 2001, Vulliamy et al. 2004) or the dyskeratosis congenita 1 gene (DKC1) (patients with the X-linked form of the disease), which encodes a protein involved in Terc stability and snoRNA processing (Mitchell et al. 1999). Both mutations result in decreased telomerase activity and shorter telomeres compared to healthy individuals (Mitchell et al. 1999, Vulliamy et al. 2001, Vulliamy et al. 2004).

Strikingly, DC patients show increased chromosomal instability with age, consistent with a faster rate of telomere loss, suggesting that DC may be a chromosomal instability syndrome produced by a defect in telomerase activity and the proper maintenance of telomeres (see Du et al., this volume). DC patients develop many of the pathologies shown for the telomerase-deficient mouse model, such as short stature, hypogonadism and infertility, defects of the skin and the hematopoietic system, bone marrow failure, and premature death. Similarly to telomerase-deficient mice, human DC is characterized by showing disease anticipation in affected progeny, demonstrating that short telomeres directly contribute to disease presentation (Vulliamy et al. 2004). In addition, a number of patients diagnosed with aplastic anemia also show mutations in the telomerase Terc and Tert genes, resulting in accelerated telomere shortening and premature death (Yamaguchi et al. 2005, Marrone et al. 2004). However, an important difference between DC patients and telomerase-deficient mice is the fact that DC patients show an elevated incidence of spontaneous cancer, while telomerase-deficient mice have an increased resistance to cancer, except for p53-deficient and TRF2 overexpressing genetic backgrounds (Gonzalez- Suarez et al.

2000, Rudolph et al. 2001, Greenberg et al. 1999, Blanco et al. 2007). Therefore, DC is a human premature ageing syndrome that closely, but not completely, recapitulates the phenotype of the telomerase-deficient mouse model. A reason for this difference may be that DC patients still retain some telomerase activity, while the telomerase knockout mouse model lacks telomerase activity.

In addition to DC and aplastic anemia patients, who have defective telomerase activity and short telomeres, a number of additional human premature ageing syndromes are also characterized by an accelerated rate of telomere loss and chromosomal instability. Interestingly, these diseases are produced by mutations in DNA repair proteins such as Nbs1 (Nijmegen breakage syndrome), Mre11 (ataxia telangiectasia-like disorder), WRN (Werner syndrome; see Davis and Kipling, this volume), BLM (Bloom syndrome), ATM (ataxia telangiectasia) (ATM), and FANC genes (Fanconi anemia) (reviewed in Blasco 2005), many of which interact with the TRF2 telomere-binding protein (reviewed in Blasco 2005). Strikingly, when mice deficient for these proteins have been generated they do not faithfully reproduce premature ageing pathologies. In fact, the ageing pathologies associated with the Werner, Bloom, and ATM syndromes have been modeled in mice only when in combination with telomerase deficiency and short telomeres in the context of the telomerase-deficient mouse model (Chang et al. 2004, Wong et al. 2003, Du et al. 2004, Mochizuki et al. 2004), suggesting that short telomeres contribute to the pathobiology of these premature-ageing diseases.

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