Telomere disease
Definition
•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 orreplacement by fat, and a proclivity for cancer.
DISEASE MECHANISM
•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.
•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.
•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.
CLINICAL MANIFESTATIONS
-Dyskeratosis Congenita
Dyskeratosis congenita is the classic telomere disease, a mainly pediatric syndrome diagnosed in the first two decades of life. Bone Marrow Failure Aplastic anemia is the most common major clinical manifestation of dyskeratosis congenita