Molecular Diagnosis and Precision Therapeutic Approaches for Telomere Biology Disorders

Telomeres are nucleo-protein structures located at the end of chromosomes that protect them from degradation. Telomeres length is maintained by the ac‐ tivity of the telomerase complex. These structures are protected by a special‐ ized protein complex named shelterin. In the absence of telomerase activity and/or protection telomeres are shortened after each round of DNA replica‐ tion. When a critical size is reached, telomeres are recognized as damaged DNA by the cell p53-dependent DNA-repair system. Persistent activation of this pathway finally results in cell apoptosis or senescence. There are a number of rare hereditary diseases caused by the presence of short‐ ened telomeres, collectively named telomeropathies or telomere biology disor‐ ders. In these diseases, cell proliferation is impaired, which results in premature aging and dysfunction of highly proliferative tissues (bone morrow, skin and other epithelia). Among them are Dyskeratosis congenita, the Hoyer‐ aal-Hreidarsson, Revesz and Coats plus syndromes, Aplastic anemia, Idiopath‐ ic pulmonary fibrosis and nonalcoholic, noninfectious liver disease. Mutations present in the genes coding for component of the telomerase and shelterin complexes and other proteins involved in telomere replication are the cause of these diseases. Clinical manifestations, causative mutations, diagnosis and pos‐ sible therapeutic approaches to these diseases will be discussed in this chapter.