The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis
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Werner syndrome (WS) is an adult onset segmental progeroid syndrome caused by mutations in the WRN gene. The WRN gene encodes a 180 kDa nuclear protein that possesses helicase and exonuclease activities. The absence of WRN protein leads to abnormalities in various DNA metabolic pathways such as DNA repair, replication and telomere maintenance. Individuals with WS generally develop normally until the third decade of life, when premature aging phenotypes and a series of age-related disorders begin to manifest. In Japan, where a founder effect has been described, the frequency of Werner heterozygotes appears to be as high as 1/180 in the general population. Due to the relatively non-specific nature of the symptoms and the lack of awareness of the condition, this disease may be under-diagnosed in other parts of the world. Genetic counseling of WS patients follows the path of other autosomal recessive disorders, with special attention needed for cancer surveillance in relatives. Molecular diagnosis of WS is made by nucleotide sequencing and, in some cases, protein analysis. It is also of potential interest to measure WRN activities in WS patients. More than 50 different disease-causing mutations in the WRN gene have been identified in WS patients from all over the world. All but one of these cases has mutations that result in the premature termination of the protein. Here we describe the clinical, molecular and biochemical characteristics of WS for use by medical professionals in a health care setting. Additional information is available through the International Registry of WS (http://www.wernersyndrome.org).
KeywordsExonuclease Activity Werner Syndrome LMNA Gene LMNA Mutation Progeroid Syndrome
This work was partially supported by the Intramural Research Program of the NIH, National Institute on Aging, and by the NIH grant CA78088 (to J.O).
- Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M (2006) Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc Natl Acad Sci USA 103:8822–8827Google Scholar
- 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 (Baltimore) 45:177–221Google Scholar
- Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298PubMedCrossRefGoogle Scholar
- Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H, Dorn T, Spiegel R, Oral EA, Abid M, Battisti C, Lucci-Cordisco E, Neri G, Steed EH, Kidd A, Isley W, Showalter D, Vittone JL, Konstantinow A, Ring J, Meyer P, Wenger SL, von HA, Wollina U, Schuelke M, Huizenga CR, Leistritz DF, Martin GM, Mian IS, Oshima J (2006) The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat 27:558–567Google Scholar
- Nakayama R, Sato Y, Masutani M, Ogino H, Nakatani F, Chuman H, Beppu Y, Morioka H, Yabe H, Hirose H, Sugimura H, Sakamoto H, Ohta T, Toyama Y, Yoshida T, Kawai A (2008) Association of a missense single nucleotide polymorphism, Cys1367Arg of the WRN gene, with the risk of bone and soft tissue sarcomas in Japan. Cancer Sci 99:333–339PubMedCrossRefGoogle Scholar
- Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D’Apice MR, Massart C, Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G, Dallapiccola B, Merlini L, Bonne G (2002) Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 71:426–431PubMedCrossRefGoogle Scholar
- Oshima J, Yu CE, Piussan C, Klein G, Jabkowski J, Balci S, Miki T, Nakura J, Ogihara T, Ells J, Smith M, Melaragno MI, Fraccaro M, Scappaticci S, Matthews J, Ouais S, Jarzebowicz A, Schellenberg GD, Martin GM (1996) Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum Mol Genet 5:1909–1913PubMedCrossRefGoogle Scholar
- Shen M, Zheng T, Lan Q, Zhang Y, Zahm SH, Wang SS, Holford TR, Leaderer B, Yeager M, Welch R, Kang D, Boyle P, Zhang B, Zou K, Zhu Y, Chanock S, Rothman N (2006) Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma among women in Connecticut. Human Genet 119:659–668CrossRefGoogle Scholar
- Sumi SM (1985) Neuropathology of Werner syndrome. In: Salk D, Fujiwara Y, Martin GM (eds) Werner’s syndrome and human aging. Plenum, New York, pp 215–218Google Scholar
- Wirtenberger M, Frank B, Hemminki K, Klaes R, Schmutzler RK, Wappenschmidt B, Meindl A, Kiechle M, Arnold N, Weber BH, Niederacher D, Bartram CR, Burwinkel B (2006) Interaction of Werner and Bloom syndrome genes with p53 in familial breast cancer. Carcinogenesis 27:1655–1660PubMedCrossRefGoogle Scholar