| Werner syndrome |
| Classification and external resources |
| ICD-10 |
E34.8 (ILDS E34.820) |
| ICD-9 |
259.8 |
| OMIM |
277700 |
| DiseasesDB |
14096 |
| MeSH |
C16.320.925 |
| GeneReviews |
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Werner syndrome has an autosomal recessive pattern of inheritance.
Werner syndrome (WS, also known as "adult progeria"[1]:573) is a rare, autosomal recessive[2][3][4] progeroid syndrome (PS), which is characterized by the appearance of premature aging.[5]
Werner syndrome is named after the German scientist Otto Werner.[6] He identified the syndrome in four siblings observed with premature aging, which he explored as the subject of his dissertation of 1904.[7]
It has a global incidence rate of less than 1 in 100,000 per live birth[3] (although incidence in Japan and Sardinia is higher, affecting 1 in 20,000-40,000 and 1 in 50,000, respectively);[8][9] there have been 1,300 reported cases.[10] Affected individuals typically grow and develop normally until puberty; the mean age of diagnosis is twenty-four, often realized when the adolescent growth spurt is not observed.[11] The youngest person diagnosed was six years old.[12] The median and mean age of death is 47-48 and 54 years, respectively;[13] the main cause of death is cardiovascular disease or cancer.[10][11]
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Contents
- 1 Characteristics
- 2 Causes
- 3 Molecular cellular biology
- 4 Treatment
- 5 Popular culture
- 6 See also
- 7 References
- 8 External links
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Characteristics [edit]
The appearance of affected individuals is abnormal. They exhibit growth retardation, short stature, premature graying of hair, alopecia (hair loss), wrinkling, prematurely aged face with a beaked nose, skin atrophy (wasting away) with scleroderma-like lesions, lipodystrophy (loss of fat tissues), abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli (around ankles). Other medical signs include change in voice (weak, hoarse, high-pitched), atrophy of gonads leading to reduced fertility, bilateral cataract (clouding of lens), premature arteriosclerosis (thickening and loss of elasticity of arteries), calcinosis (calcium deposits in blood vessels), atherosclerosis (blockage of blood vessels), type 2 diabetes, osteoporosis (loss of bone mass), telangiectasia, and malignancies.[3][10] In fact, the prevalence of rare cancers, such as meningiomas, are increased in individuals with Werner syndrome.[14]
Causes [edit]
Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the eponymous gene, WRN; the only gene currently attributed to cause Werner syndrome.[12][13] WRN, which lies on chromosome 8 in humans,[15] encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication.[4][8] Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.
Mutations which cause Werner syndrome all occur at the regions of the gene which encode for protein, and not at non-coding regions.[16] These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With less mRNA, less is available to be translated into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein leading to the loss of its nuclear localization signal sequence, thus it is no longer transported into the nucleus where it interacts with the DNA. This leads to a reduction in DNA repair.[16] Furthermore, mutated proteins are more likely to be degraded than normal WRNp.[8] Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increase the survival of these disfunctional cells.[17]
Cells of affected individuals have reduced lifespan in culture,[18] have more chromosome breaks and translocations[19] and extensive deletions.[20] These mutations may in turn cause more RecQ-independent aging phenotypes.
Molecular cellular biology [edit]
The WRNp protein have been shown to be associated with RAD52 (a recombination mediator protein),[21] the Ku complex,[22] components of the DNA replication complex (DNA polymerase,[23][24] human replication protein A,[25] proliferating cell nuclear antigen[26] and topoisomerase I),[26] p53,[27] and TRF2 (a telomeric repeat binding factor).[28]
Treatment [edit]
In 2010, vitamin C supplementation was found to reverse the premature aging and several tissue dysfunctions in a genetically modified mouse model of the disease. Vitamin C supplementation also appeared to normalize several age-related molecular markers such as the increased levels of the transcription factor NF-κB. Vitamin C decreases activity of genes activated in human Werner syndrome, and increases gene activity involved in tissue repair.[29] Vitamin C supplementation is suspected to be beneficial in the treatment of human Werner syndrome, although there was no evidence of anti-aging activity in nonmutant mice.[29]
Popular culture [edit]
On the episode "Stargazer in a Puddle" from the series Bones, the victim had Werner syndrome.
Werner syndrome was featured in the film Jack, starring Robin Williams, in which his character aged four times faster than normal.
In an early cut scene from the game Metal Gear Solid 4, Hal "Otacon" Emmerich cites "classic Werner syndrome" as the most likely cause of Solid Snake's premature aging, though he goes on to say that testing had been inconclusive.
In season 3 episode 9, "The Ballad of Kevin and Tess", of TV show The 4400, Kevin is said to have Werner syndrome to hide his real condition from the public.
In The Invisible Man (2000 TV series) season 1 episode 6, "Impetus", the new character Gloria has an experimentally altered type of Werner syndrome that causes it to become contagious.
See also [edit]
- Accelerated aging disease
- Biogerontology
- Cockayne syndrome
- DNA repair
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- Degenerative disease
- Genetic disorder
- Life extension
- Progeria
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- Senescence
- Xeroderma pigmentosum
- List of cutaneous conditions
- Progeroid syndrome
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References [edit]
- ^ James, William; Berger, Timothy; Elston, Dirk (2005).Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
- ^ Ozgenc A, Loeb LA (Sep 2005). "Current advances in unraveling the function of the Werner syndrome protein". Mutation research 577 (1–2): 237–51. doi:10.1016/j.mrfmmm.2005.03.020. PMID 15946710.
- ^ a b c Hasty, P.; Campisi, J; Hoeijmakers, J; Van Steeg, H; Vijg, J (2003). "Aging and Genome Maintenance: Lessons from the Mouse?". Science 299 (5611): 1355–9. doi:10.1126/science.1079161. PMID 12610296.
- ^ a b Gray, Matthew D.; Shen, Jiang-Cheng; Kamath-Loeb, Ashwini S.; Blank, A.; Sopher, Bryce L.; Martin, George M.; Oshima, Junko; Loeb, Lawrence A. (1997). "The Werner syndrome protein is a DNA helicase". Nature Genetics 17 (1): 100–3. doi:10.1038/ng0997-100. PMID 9288107.
- ^ Gray MD, Shen JC, Kamath-Loeb AS, Blank A, Sopher BL, Martin GM, Oshima J, Loeb LA (Sep 1997). "The Werner syndrome protein is a DNA helicase". Nature Genetics 17 (1): 100–3. doi:10.1038/ng0997-100. PMID 9288107.
- ^ synd/892 at Who Named It?
- ^ "On cataract in conjunction with scleroderma. Otto Werner, doctoral dissertation, 1904, Royal Ophthalmology Clinic, Royal Christian Albrecht University of Kiel". Advances in experimental medicine and biology 190: 1–14. 1985. PMID 3909762.
- ^ a b c "Werner syndrome". Genetics Home Reference. Retrieved 18 March 2013.
- ^ Masala, MV; Scapaticci, S; Olivieri, C; Pirodda, C; Montesu, MA; Cuccuru, MA; Pruneddu, S; Danesino, C et al. (2007). "Epidemiology and clinical aspects of Werner's syndrome in North Sardinia: Description of a cluster". European journal of dermatology : EJD 17 (3): 213–6. doi:10.1684/ejd.2007.0155. PMID 17478382.
- ^ a b c Navarro, CL; Cau, P; Lévy, N (2006). "Molecular bases of progeroid Yes syndromes". Human molecular genetics. 15 Spec No 2: R151–61. doi:10.1093/hmg/ddl214. PMID 16987878.
- ^ a b Epstein, CJ; Martin, GM; Schultz, AL; Motulsky, AG (1966). "Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process". Medicine 45 (3): 177–221. PMID 5327241.
- ^ a b Oshima J, Martin GM, Hisama FM (February 2012). Werner Syndrome. PMID 20301687. NBK1514. InPagon RA, Bird TD, Dolan CR, et al., ed. (1993–). GeneReviews™ [Internet]. Seattle WA: University of Washington, Seattle.
- ^ a b Oshima J, Martin GM, Hisama FM. Werner Syndrome. 2002 Dec 2 [Updated 2012 Dec 13]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from:http://www.ncbi.nlm.nih.gov/books/NBK1514/
- ^ Goto, M; Miller, RW; Ishikawa, Y; Sugano, H (1996). "Excess of rare cancers in Werner syndrome (adult progeria)". Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 5 (4): 239–46. PMID 8722214.
- ^ Goto M, Rubenstein M, Weber J, Woods K, Drayna D (Feb 1992). "Genetic linkage of Werner's syndrome to five markers on chromosome 8". Nature 355 (6362): 735–8. doi:10.1038/355735a0. PMID 1741060.
- ^ a b Huang, S; Lee, L; Hanson, NB; Lenaerts, C; Hoehn, H; Poot, M; Rubin, CD; Chen, DF et al. (2006). "The spectrum of WRN mutations in Werner syndrome patients". Human mutation 27 (6): 558–67. doi:10.1002/humu.20337. PMC 1868417. PMID 16673358.
- ^ Spillare, EA; Robles, AI; Wang, XW; Shen, JC; Yu, CE; Schellenberg, GD; Harris, CC (1999). "P53-mediated apoptosis is attenuated in Werner syndrome cells". Genes & development 13 (11): 1355–60. doi:10.1101/gad.13.11.1355. PMC 316776. PMID 10364153.
- ^ Martin, GM; Sprague, CA; Epstein, CJ (1970). "Replicative life-span of cultivated human cells. Effects of donor's age, tissue, and genotype". Laboratory investigation; a journal of technical methods and pathology 23 (1): 86–92. PMID 5431223.
- ^ Salk, D; Au, K; Hoehn, H; Martin, GM (1981). "Cytogenetics of Werner's syndrome cultured skin fibroblasts: Variegated translocation mosaicism". Cytogenetics and cell genetics 30 (2): 92–107. PMID 7273860.
- ^ Fukuchi, K; Martin, GM; Monnat Jr, RJ (1989). "Mutator phenotype of Werner syndrome is characterized by extensive deletions". Proceedings of the National Academy of Sciences of the United States of America 86 (15): 5893–7. doi:10.1073/pnas.86.15.5893. PMC 297737. PMID 2762303.
- ^ Baynton, K; Otterlei, M; Bjørås, M; Von Kobbe, C; Bohr, VA; Seeberg, E (2003). "WRN interacts physically and functionally with the recombination mediator protein RAD52". The Journal of biological chemistry 278 (38): 36476–86. doi:10.1074/jbc.M303885200. PMID 12750383.
- ^ Cooper, MP; Machwe, A; Orren, DK; Brosh, RM; Ramsden, D; Bohr, VA (2000). "Ku complex interacts with and stimulates the Werner protein". Genes & development 14 (8): 907–12. PMC 316545. PMID 10783163.
- ^ Harrigan, JA; Opresko, PL; Von Kobbe, C; Kedar, PS; Prasad, R; Wilson, SH; Bohr, VA (2003). "The Werner syndrome protein stimulates DNA polymerase beta strand displacement synthesis via its helicase activity". The Journal of biological chemistry 278 (25): 22686–95. doi:10.1074/jbc.M213103200. PMID 12665521.
- ^ Kamath-Loeb, AS; Johansson, E; Burgers, PM; Loeb, LA (2000). "Functional interaction between the Werner Syndrome protein and DNA polymerase delta". Proceedings of the National Academy of Sciences of the United States of America 97 (9): 4603–8. doi:10.1073/pnas.97.9.4603. PMC 18279. PMID 10781066.
- ^ Brosh Jr, RM; Orren, DK; Nehlin, JO; Ravn, PH; Kenny, MK; Machwe, A; Bohr, VA (1999). "Functional and physical interaction between WRN helicase and human replication protein A". The Journal of biological chemistry 274 (26): 18341–50. doi:10.1074/jbc.274.26.18341. PMID 10373438.
- ^ a b Lebel, M; Spillare, EA; Harris, CC; Leder, P (1999). "The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I". The Journal of biological chemistry 274 (53): 37795–9. doi:10.1074/jbc.274.53.37795. PMID 10608841.
- ^ Blander, G.; Kipnis, J; Leal, JF; Yu, CE; Schellenberg, GD; Oren, M (1999). "Physical and Functional Interaction between p53 and the Werner's Syndrome Protein". Journal of Biological Chemistry 274 (41): 29463–9. doi:10.1074/jbc.274.41.29463. PMID 10506209.
- ^ Machwe, A; Xiao, L; Orren, DK (2004). "TRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA". Oncogene 23 (1): 149–56. doi:10.1038/sj.onc.1206906. PMID 14712220.
- ^ a b Massip, L.; Garand, C.; Paquet, E. R.; Cogger, V. C.; O'Reilly, J. N.; Tworek, L.; Hatherell, A.; Taylor, C. G.; Thorin, E.; Zahradka, P.; Le Couteur, D. G.; Lebel, M. (2009-09-09). "Vitamin C restores healthy aging in a mouse model for Werner syndrome". The FASEB Journal 24 (1): 158–172. doi:10.1096/fj.09-137133. Retrieved 2011-10-24.
External links [edit]
This article incorporates public domain text from The U.S. National Library of Medicine
- Werner Syndrome from GeneReviews™, contains extensive information on the disorder
- Werner syndrome at libero.it
- DNA Repair at rcn.com
- Segmental Progeria at benbest.com
- WRN at the GenAge database.
- werner at NIH/UW GeneTests
- 00421 at CHORUS
- Cancer.Net: Werner Syndrome
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Metabolic disease: DNA replication and DNA repair-deficiency disorder
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| DNA replication |
- Separation/initiation: RNASEH2A
- Aicardi–Goutières syndrome 4
- Termination/telomerase: DKC1
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| DNA repair |
| Nucleotide excision repair |
- Cockayne syndrome/DeSanctis–Cacchione syndrome
- Thymine dimer
- IBIDS syndrome
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| MSI/DNA mismatch repair |
- Hereditary nonpolyposis colorectal cancer
- Muir–Torre syndrome
- Mismatch repair cancer syndrome
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| MRN complex |
- Ataxia telangiectasia
- Nijmegen breakage syndrome
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| Other |
- RecQ helicase
- Bloom syndrome
- Werner syndrome
- Rothmund–Thomson syndrome/Rapadilino syndrome
- Fanconi anemia
- Li-Fraumeni syndrome
- Severe combined immunodeficiency
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See also: DNA replication, DNA repair
- B structural
- perx
- skel
- cili
- mito
- nucl
- sclr
- DNA/RNA/protein synthesis
- membrane
- transduction
- trfk
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Progeroid syndromes
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| DNA repair |
| RecQ-associated |
- Werner syndrome
- Bloom syndrome
- Rothmund–Thomson syndrome
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| NER protein-associated |
- Cockayne syndrome
- Xeroderma pigmentosum
- Trichothiodystrophy
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| Lamin A/C |
- Hutchinson–Gilford progeria syndrome
- Restrictive dermopathy
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| Other/Related disorders |
- Li–Fraumeni syndrome
- Rapadilino syndrome
- Baller-Gerold syndrome
- DeSanctis–Cacchione syndrome
- Nijmegen breakage syndrome
- Fanconi anemia
- Dyskeratosis congenita
- Ataxia telangiectasia
- De Barsy syndrome
- PIBI(D)S syndrome
- BIDS syndrome
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See also: DNA replication and repair-deficiency disorder
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