Erosion of telomeric single-stranded overhang in patients with aplastic anaemia carrying telomerase complex mutations

Loss-of-function mutations in telomerase complex genes reduce telomerase activity and shorten overall telomere length in leucocytes, and they can clinically manifest as bone marrow failure (aplastic anaemia and dyskeratosis congenita) and familial pulmonary fibrosis. Telomeres are constituted of double-stranded tandem TTAGGG repeats followed by a 3' G-rich single-stranded overhang, a crucial telomeric structural component responsible for the t-loop formation.

We investigated the length of telomeric overhangs in 25 healthy individuals from 0 to 76 years of age, 16 patients with aplastic anaemia, and 13 immediate relatives using a non-denaturing in-gel method and the telomere-oligonucleotide ligation assay.

Telomeric overhang lengths were constant from birth to eighth decade of life in healthy subjects, in contrast to overall telomere length, which shortened with ageing. Most patients with marrow failure and a telomerase gene mutation showed marked erosion of telomeric overhang associated with critically short telomeres; in other aplastic patients with normal genotypes, normal overall telomere lengths and who responded to immunosuppressive therapy, telomeric overhangs were maintained.

Telomeric overhang erosion does not participate in physiological ageing but support a role for eroded telomeric overhangs and abnormal telomere structure in pathological shortening of telomeres, especially caused by loss-of-function telomerase mutations. Disrupted telomere structure caused by short telomeric overhangs may contribute to the mechanisms of abnormal haematopoietic compartment senescence and chromosomal instability in human bone marrow failure.