Dyskeratosis Congenita - Pathophysiology

Pathophysiology

Though the exact pathology of the disease is not yet fully understood, most evidence points to dyskeratosis congenita being primarily a disorder of poor telomere maintenance. Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate telomerase RNA component (TERC).

Telomerase is a reverse transcriptase which maintains a specific repeat sequence of DNA, the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal end-shortening that occurs during normal DNA replication. This end-shortening is the result of the eukaryotic DNA polymerases having no mechanism for synthesizing the final nucleotides present on the end of the "lagging strand" of double stranded DNA. DNA polymerase can only synthesize new DNA from an old DNA strand in the 5'->3' direction. Given that DNA has two strands that are complementary, one strand must be 5'->3' while the other is 3'->5'. This inability to synthesize in the 3'->5' directionality is compensated with the use of Okazaki fragments, short pieces of DNA that are synthesized 5'->3' from the 3'->5' as the replication fork moves. As DNA polymerase requires RNA primers for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized. When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed. Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases.

Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres. With TERC levels down, telomere maintenance during development suffers accordingly. In humans, telomerase is inactive in most cell types after early development (except in extreme cases such as cancer). Thus, if telomerase is not able to efficiently affect the DNA in the beginning of life, chromosomal instability becomes a grave possibility in individuals much earlier than would be expected.

A study shows that proliferative defects in DC skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC. Experimental Dermatology 2010; 19: 279–288