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In telomere diseases (also called telomeropathies or telomere spectrum disorders), organ dysfunction is caused by loss of the ends of chromosomes, a process termed accelerated telomere attrition. Inadequate repair or insufficient protection of telomeres and their resulting erosion induces cell death, deficient cell proliferation, and chromosome instability; affected tissues show defective organ regeneration, fibrosis or replacement by fat, and a proclivity for cancer. A variety of regenerative disorders affecting especially the bone marrow, lungs, liver, and skin share telomere dysfunction and loss as their common molecular mechanism. It is important to note that telomeres appear to shorten with time based on cross-sectional data of average telomere length in groups of people at different ages. However, limited data exist about telomere shortening longitudinally in individual people. Despite shortening of telomeres over time, normal aging is not associated with the development of disease from short telomeres. In normal aging, sufficient stem cell number and function are maintained to sustain vital processes. Even a patient who receives a limited number of hematopoietic cells from an adult donor is capable of maintaining normal hematopoiesis for many years, at least in part related to normal telomerase function and telomere repair. When symptoms develop as a consequence of short telomeres, a disease process is at work.


Telomeres, the physical termini of linear chromosomes, are repeated hexanucleotide sequences physically associated with specific proteins. Telomeres function to protect the chromosome ends against recognition as damaged or infectious DNA by the DNA repair machinery (Fig. 470-1). During mitosis, the DNA polymerase employs an RNA oligonucleotide with a 3' hydroxyl group to prime replication. The primer dissociates as the DNA polymerase advances along the template strand, and a gap is left at the ends of linear DNA molecules: the newly synthesized DNA strand is necessarily shorter than the original template—the “end-replication problem.” Chromosome erosion is thus inevitable with mitotic cell division, but the noncoding telomeric long, repetitive structure buffers loss of genetic information. In human cells, telomeres are composed of hundreds to thousands of TTAGGG tandem repeats in the leading and CCCTAA in the lagging DNA strand. At birth, telomeres are relatively long but they inexorably shorten with chronological aging (Fig. 470-1). In an individual cell, critically short telomere length triggers the p53 pathway, usually leading to proliferative arrest, senescence, and apoptosis. Telomere loss is the molecular basis for the “Hayflick phenomenon,” the limit to cell division and thus to cell proliferation in tissue culture. If a cell overrides proliferation arrest, extremely short telomeres may engage the DNA damage repair machinery, and chromosome end-to-end fusions, chromosome breaks, aneuploidy, and chromosome instability may occur. In addition to the telomere repeated sequences, a group of specialized proteins, collectively termed shelterins, directly bind to or indirectly associate with telomeres, assisting in the organization of the telomere tertiary structure and inhibiting activity of DNA damage response proteins (Fig. 470-1).


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