Dyskeratosis congenita: Difference between revisions

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==Overview==
==Overview==
'''Dyskeratosis congenita''' (DKC), also called '''Zinsser-Cole-Engman syndrome''',<ref name=omim>{{OMIM|305000}}</ref><ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. ISBN 0-7216-2921-0.</ref>{{rp|570}} is a rare progressive [[congenital disorder]] that in some ways resembles premature aging (similar to [[progeria]]). The disease mainly affects the [[integumentary system]], the organ system that protects the body from damage, with a major consequence being anomalies of the [[bone marrow]].
'''Dyskeratosis congenita''' (DKC), also called '''Zinsser-Cole-Engman syndrome''',<ref name=omim>{{OMIM|305000}}</ref><ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. ISBN 0-7216-2921-0.</ref>{{rp|570}} is a rare progressive [[congenital disorder]] that in some ways resembles premature aging (similar to [[progeria]]). The disease mainly affects the [[integumentary system]], the organ system that protects the body from damage, with a major consequence being anomalies of the [[bone marrow]].


==Pathophysiology==
==Pathophysiology==
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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<ref>Gourronc, F. A., Robertson, M. M., Herrig, A. K., Lansdorp, P. M., Goldman, F. D. and Klingelhutz, A. J. (2010), [http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0625.2009.00916.x/abstract Proliferative defects in dyskeratosis congenita 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, 19: 279–288. {{doi|10.1111/j.1600-0625.2009.00916.x}}</ref>
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<ref>Gourronc, F. A., Robertson, M. M., Herrig, A. K., Lansdorp, P. M., Goldman, F. D. and Klingelhutz, A. J. (2010), [http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0625.2009.00916.x/abstract Proliferative defects in dyskeratosis congenita 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, 19: 279–288. {{doi|10.1111/j.1600-0625.2009.00916.x}}</ref>
===Genetics===
Of the components of the telomerase RNA component (TERC), one of key importance is the [[SnoRNA#H.2FACA_box|box H/ACA]] domain. This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole. The [[mammal]]ian H/ACA [[ribonucleoprotein]] contains four [[protein]] subunits: dyskerin, Gar1, Nop10, and Nhp2. [[Mutation]]s in Nop10,<ref name="pmid17507419" /> Nhp2<ref name="pmid18523010">{{cite journal |author=Vulliamy T, Beswick R, Kirwan M, "et al." |title=Mutations in the telomerase component Nhp2 cause the premature ageing syndrome dyskeratosis congenita. |journal=Proc Natl Acad Sci USA|volume=105 |year=2008 |month=June|pmid=18523010|url=http://www.pnas.org/content/105/23/8073.long |doi=10.1073/pnas.0800042105 |issue=23 |pages=8073–8 |pmc=2430361 }}</ref> and dyskerin1<ref name="pmid9590285" /> have all been shown to lead to DKC-like symptoms.

Revision as of 15:49, 24 July 2012

Dyskeratosis congenita
ICD-10 Q82.8
ICD-9 757.39
OMIM 305000
DiseasesDB 30105
eMedicine derm/111 
MeSH D019871

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Overview

Dyskeratosis congenita (DKC), also called Zinsser-Cole-Engman syndrome,[1][2]:570 is a rare progressive congenital disorder that in some ways resembles premature aging (similar to progeria). The disease mainly affects the integumentary system, the organ system that protects the body from damage, with a major consequence being anomalies of the bone marrow.

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.[3] 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.[4] 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.[4][5]

Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres.[3][6][7] 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).[8] 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.[citation needed]

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[9]


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,[6] Nhp2[10] and dyskerin1[7] have all been shown to lead to DKC-like symptoms.

  1. ↑ Online Mendelian Inheritance in Man (OMIM) 305000
  2. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
  3. ↑ 3.0 3.1 Vulliamy T, Marrone A, Goldman F; et al. (2001). "The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita". Nature. 413 (6854): 432–435. doi:10.1038/35096585. PMID 11574891. Unknown parameter |month= ignored (help)
  4. ↑ 4.0 4.1 Greider, CW. (1996). "Telomere length regulation". Annu. Rev. Biochem. 65: 337–365. doi:10.1146/annurev.bi.65.070196.002005?url_ver=Z39.88-2003. PMID 8811183. Unknown parameter |month= ignored (help)
  5. ↑ Wason, James; et al. (2004). Molecular Biology of the Gene. 5th ed. Annu. Rev. Biochem. San Francisco: Pearson Education, Inc.
  6. ↑ 6.0 6.1 Walne AJ, Vulliamy T, Marrone A; et al. (2007). "Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10". Hum Mol Genet. 16 (13): 1619–29. doi:10.1093/hmg/ddm111. PMC 2882227. PMID 17507419. Unknown parameter |month= ignored (help)
  7. ↑ 7.0 7.1 Heiss NS, Knight SW, Vulliamy TJ; et al. (1998). "X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions". Nat. Genet. 19 (1): 32–38. doi:10.1038/ng0598-32. PMID 9590285. Unknown parameter |month= ignored (help)
  8. ↑ Wong J, Collins K (2006). "Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita". Genes Dev. 20 (20): 2848–2858. doi:10.1101/gad.1476206. PMC 1619937. PMID 17015423. Unknown parameter |month= ignored (help)
  9. ↑ Gourronc, F. A., Robertson, M. M., Herrig, A. K., Lansdorp, P. M., Goldman, F. D. and Klingelhutz, A. J. (2010), Proliferative defects in dyskeratosis congenita 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, 19: 279–288. doi:10.1111/j.1600-0625.2009.00916.x
  10. ↑ Vulliamy T, Beswick R, Kirwan M; et al. (2008). "Mutations in the telomerase component Nhp2 cause the premature ageing syndrome dyskeratosis congenita". Proc Natl Acad Sci USA. 105 (23): 8073–8. doi:10.1073/pnas.0800042105. PMC 2430361. PMID 18523010. Unknown parameter |month= ignored (help)
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