Dyskeratosis Congenita

What is Dyskeratosis Congenita?

Dyskeratosis congenita (DKC), also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder which results in premature aging similar to what is seen in progeria. The disease mainly affects the integumentary system with a major consequence being anomalies of the bone marrow.

DKC can be characterized by cutaneous pigmentation, premature graying, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer. Many of these symptoms are characteristic of geriatrics, and those carrying the more serious forms of the disease often have significantly shortened lifespans.

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Dyskeratosis Congenita 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, in higher eukaryotes, 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 chromosome 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 following the stages 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.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Dyskeratosis congenita" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.

Dyskeratosis Congenita Genetics

Of the components of the telomerase RNA component (TERC), one of key importance is the box H/ACA domain. This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole. The mammalian H/ACA ribonucleoprotein contains four protein subunits: dyskerin, Gar1, Nop10, and Nhp2. Mutations in Nop10 and dyskerin1 has shown that these mutations affect telomerase activity by negatively affecting pre-RNP assembly and maturation of human telomerase RNA. Nonetheless, mutations which directly affect the telomerase RNA components would presumably exist and should also cause premature aging or DKC-like symptoms. Indeed, three families with mutations in the human TERC gene have been studied with intriguing results. In two of these families, two family-specific single nucleotide polymorphisms were present while in the other there persisted a large-scale deletion (821 base pairs of DNA) on chromosome 3 which includes 74 bases coding for a section of the H/ACA domain. These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance. Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Dyskeratosis congenita" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.