Exotic genetic diseases often provide important clues for the aging process, and I have previously discussed implications of Hutchinson-Gilford progeria and Werner Syndrome in this Blog. This time, a research item on Hoyeraal-Hreidarsson Syndrome(HHS) came to my attention. “Hoyeraal-Hreidarsson syndrome is a multisystem disorder affecting males and is characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation. HHS is a severe variant of dyskeratosis congenita(ref).”(ref). HHS is “mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, failure, and (ref).” Telomere shortening and damage is the 12th theory of aging covered in my Anti-Aging Firewalls Treatise.
The key conclusion of the new research is “Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR (DNA damage response) and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease(ref).” The problem in the case of HHS is apparently due to diminished 3â€² overhangs which are part of telomeric DNA, that is, defective telomere caps. Telomerase works by adding telomeric repeats off of the 3” overhangs and, if the overhangs are not normal, cannot do its job of extending telomeres. The researchers tracked the problem down to mutations in the telomerase subunits and in the Shelterin component Tin2. Shelterin is a protein complex that is essential for shaping and protecting human telomeres. It has six components: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1. Shelterin is important for enabling cells to distinguish telomeres from sites of DNA damage.
The study demonstrates the complexity involved in telomerase activation and that many pathways can contribute to either telomere extension or shortening. The devil is in the details. The results are related to those posted in previous blog entries: More research progress on telomerase, and Stem cells, telomeres and telomerase and DNA repair.