Telomere-driven diseases and telomere-targeting therapies

Abstract

Martínez and Blasco review the molecular mechanisms underlying diseases associated with telomere dysfunction, including telomeropathies, age-related disorders, and cancer. Current and future therapeutic strategies to treat and prevent these diseases, including preclinical development of telomere-targeted therapies using mouse models, are discussed.

Long-Term Follow-Up of a Case with Dyskeratosis Congenita Caused by NHP2-V126M/X154R Mutation: Genotype-Phenotype Association

“…The first defined patient with a Y139H homozygous mutation was also a Turkish man, who had nail dystrophy, thrombocytopenia, testicular atrophy, opportunistic infections, growth and mental retardation, liver cirrhosis, and intracranial calcification [10]. Furthermore, pulmonary fibrosis was reported in patients with germline NHP2 variants [5]. The major problem of our patient with a NHP2-V126M/X154R compound heterozygous mutation was thrombocytopenia and severe bone marrow failure developed during a period of 20 years.…”

“…Patients with DC have a very short telomere defined by a telomere of less than the first percentile for their age [4]. Short telomeres block the proliferative capacity of stem cells, affecting their potential to regenerate tissues, trigger the development of age-associated diseases, and induce chromosomal instability that can contribute to cancer predisposition [5]. Gene mutations associated with DC, such as DC1, TERC, TERT, TINF2, NHP2, NOP10, ACD, CTC1, NAF1, PARN, POT1, RTEL1, STN1, and WRAP53, have been identified in about 70% of patients [2, 3].…”

The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging

“…In terms of causality, several studies using animals with genetic mutations modeling human telomere syndromes have established the causal role of telomere loss in organismal aging, and have demonstrated that genetic restoration of telomerase (a specialized telomere synthesizing enzyme) can prevent premature aging in telomerase‐deficient mice . Taken together, these discoveries have stimulated the development of preclinical telomere‐targeted therapeutic approaches to delay aging …”

Telomere biology in aging and cancer: early history and perspectives

“…Genetic diseases caused by malfunction of the telomere maintenance pathway have been increasingly reported and are collectively called the telomere syndromes (Armanios and Blackburn, 2012) or telomeropathies (Opresko and Shay, 2017). Mutations in genes known to function in telomere maintenance have now been identified in a variety of human genes involved in telomerase function (TR/TERC, TERT, DKC1, NOP10/NOLA3, NHP2/NOLA2, PARN, NAF1 and TCAB1/WRAP53) and telomere protection and replication (TIN2, RTEL1, POT1, CTC1, Apollo and TPP1) (Blackburn et al, 2015;Martínez and Blasco, 2017;Opresko and Shay, 2017). The cause of the telomere syndromes has been linked to the failure of stem cell replenishment, which requires a functional telomere maintenance pathway (Blackburn et al, 2015).…”