Skip to main content

Advertisement

SpringerLink
Log in

The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis

  • Review Article
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

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).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • 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 103:8822–8827

    Google Scholar 

  • Bohr VA (2005) Deficient DNA repair in the human progeroid disorder, Werner syndrome. Mutat Res 577:252–259

    PubMed  CAS  Google Scholar 

  • Bohr VA, Metter EJ, Harrigan JA, von Kobbe C, Liu JL, Gray MD, Majumdar A, Wilson DM, Seidman MM (2004) Werner syndrome protein 1367 variants and disposition towards coronary artery disease in Caucasian patients. Mech Ageing Dev 125:491–496

    Article  PubMed  CAS  Google Scholar 

  • Broers JL, Ramaekers FC, Bonne G, Yaou RB, Hutchison CJ (2006) Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev 86:967–1008

    Article  PubMed  CAS  Google Scholar 

  • Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J (2003) LMNA mutations in atypical Werner’s syndrome. Lancet 362:440–445

    Article  PubMed  CAS  Google Scholar 

  • Ding SL, Yu JC, Chen ST, Hsu GC, Shen CY (2007) Genetic variation in the premature aging gene WRN: a case-control study on breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 16:263–269

    Article  PubMed  CAS  Google 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) 45:177–221

    CAS  Google 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 423:293–298

    Article  PubMed  CAS  Google Scholar 

  • Esteller M (2007) Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet 16:R50–R59

    Article  PubMed  CAS  Google Scholar 

  • Futami K, Ishikawa Y, Goto M, Furuichi Y, Sugimoto M (2008) Role of Werner syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells. Cancer Sci 99:843–848

    Article  PubMed  CAS  Google Scholar 

  • Goto M (1997) Hierarchical deterioration of body systems in Werner’s syndrome: implications for normal ageing. Mech Ageing Dev 98:239–254

    Article  PubMed  CAS  Google Scholar 

  • Goto M, Miller RW, Ishikawa Y, Sugano H (1996) Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 5:239–246

    PubMed  CAS  Google Scholar 

  • Goto M, Imamura O, Kuromitsu J, Matsumoto T, Yamabe Y, Tokutake Y, Suzuki N, Mason B, Drayna D, Sugawara M, Sugimoto M, Furuichi Y (1997) Analysis of helicase gene mutations in Japanese Werner’s syndrome patients. Hum Genet 99:191–193

    Article  PubMed  CAS  Google Scholar 

  • Goto M, Yamabe Y, Shiratori M, Okada M, Kawabe T, Matsumoto T, Sugimoto M, Furuichi Y (1999) Immunological diagnosis of Werner syndrome by down-regulated and truncated gene products. Hum Genet 105:301–307

    Article  PubMed  CAS  Google Scholar 

  • Gray MD, Wang L, Youssoufian H, Martin GM, Oshima J (1998) Werner helicase is localized to transcriptionally active nucleoli of cycling cells. Exp Cell Res 242:487–494

    Article  PubMed  CAS  Google Scholar 

  • Harrigan JA, Fan J, Momand J, Perrino FW, Bohr VA, Wilson DM III (2007) WRN exonuclease activity is blocked by DNA termini harboring 3′ obstructive groups. Mech Ageing Dev 128:259–266

    Article  PubMed  CAS  Google Scholar 

  • Hirai M, Suzu S, Hinokio Y, Yamada T, Yoshizumi S, Suzuki C, Satoh J, Oka Y (2005) WRN gene 1367 Arg allele protects against development of type 2 diabetes mellitus. Diabetes Res Clin Pract 69:287–292

    Article  PubMed  CAS  Google Scholar 

  • Hisama FM, Bohr VA, Oshima J (2006) WRN’s tenth anniversary. Sci Aging Knowledge Environ 2006:e18

    Article  Google 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 27:558–567

  • Ishikawa Y, Miller RW, Machinami R, Sugano H, Goto M (2000) Atypical osteosarcomas in Werner Syndrome (adult progeria). Jpn J Cancer Res 91:1345–1349

    PubMed  CAS  Google Scholar 

  • Kamath-Loeb AS, Welcsh P, Waite M, Adman ET, Loeb LA (2004) The enzymatic activities of the Werner syndrome protein are disabled by the amino acid polymorphism R834C. J Biol Chem 279:55499–55505

    Article  PubMed  CAS  Google Scholar 

  • Lee JW, Kusumoto R, Doherty KM, Lin GX, Zeng W, Cheng WH, von Kobbe C, Brosh RM Jr, Hu JS, Bohr VA (2005) Modulation of Werner syndrome protein function by a single mutation in the conserved RecQ domain. J Biol Chem 280:39627–39636

    Article  PubMed  CAS  Google Scholar 

  • Mohaghegh P, Hickson ID (2002) Premature aging in RecQ helicase-deficient human syndromes. Int J Biochem Cell Biol 34:1496–1501

    Article  PubMed  CAS  Google Scholar 

  • Mori H, Tomiyama T, Maeda N, Ozawa K, Wakasa K (2003) Lack of amyloid plaque formation in the central nervous system of a patient with Werner syndrome. Neuropathology 23:51–56

    Article  PubMed  Google Scholar 

  • Moser MJ, Kamath-Loeb AS, Jacob JE, Bennett SE, Oshima J, Monnat RJ Jr (2000) WRN helicase expression in Werner syndrome cell lines. Nucleic Acids Res 28:648–654

    Article  PubMed  CAS  Google 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 99:333–339

    Article  PubMed  Google Scholar 

  • Nakura J, Wijsman EM, Miki T, Kamino K, Yu CE, Oshima J, Fukuchi K, Weber JL, Piussan C, Melaragno MI (1994) Homozygosity mapping of the Werner syndrome locus (WRN). Genomics 23:600–608

    Article  PubMed  CAS  Google 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 71:426–431

    Article  PubMed  CAS  Google Scholar 

  • Opresko PL, Cheng WH, von Kobbe C, Harrigan JA, Bohr VA (2003) Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process. Carcinogenesis 24:791–802

    Article  PubMed  CAS  Google 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 5:1909–1913

    Article  PubMed  CAS  Google Scholar 

  • Postiglione A, Soricelli A, Covelli EM, Iazzetta N, Ruocco A, Milan G, Santoro L, Alfano B, Brunetti A (1996) Premature aging in Werner’s syndrome spares the central nervous system. Neurobiol Aging 17:325–330

    Article  PubMed  CAS  Google Scholar 

  • Rubin CD, Zerwekh JE, Reed-Gitomer BY, Pak CY (1992) Characterization of osteoporosis in a patient with Werner’s syndrome. J Am Geriatr Soc 40:1161–1163

    PubMed  CAS  Google Scholar 

  • Satoh M, Imai M, Sugimoto M, Goto M, Furuichi Y (1999) Prevalence of Werner’s syndrome heterozygotes in Japan. Lancet 353:1766

    Article  PubMed  CAS  Google 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 119:659–668

    Article  CAS  Google 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 215–218

    Google Scholar 

  • Suzuki T, Shiratori M, Furuichi Y, Matsumoto T (2001) Diverged nuclear localization of Werner helicase in human and mouse cells. Oncogene 20:2551–2558

    Article  PubMed  CAS  Google Scholar 

  • Uhrhammer NA, Lafarge L, Dos SL, Domaszewska A, Lange M, Yang Y, Aractingi S, Bessis D, Bignon YJ (2006) Werner syndrome and mutations of the WRN and LMNA genes in France. Hum Mutat 27:718–719

    Article  PubMed  Google Scholar 

  • Wang L, Evans AE, Ogburn CE, Youssoufian H, Martin GM, Oshima J (1999) Werner helicase expression in human fetal and adult aortas. Exp Gerontol 34:935–941

    Article  PubMed  CAS  Google 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 27:1655–1660

    Article  PubMed  CAS  Google Scholar 

  • Yamabe Y, Sugimoto M, Satoh M, Suzuki N, Sugawara M, Goto M, Furuichi Y (1997) Down-regulation of the defective transcripts of the Werner’s syndrome gene in the cells of patients. Biochem Biophys Res Commun 236:151–154

    Article  PubMed  CAS  Google Scholar 

  • Ye L, Miki T, Nakura J, Oshima J, Kamino K, Rakugi H, Ikegami H, Higaki J, Edland SD, Martin GM, Ogihara T (1997) Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population. Am J Med Genet 68:494–498

    Article  PubMed  CAS  Google Scholar 

  • Yeong EK, Yang CC (2004) Chronic leg ulcers in Werner’s syndrome. Br J Plast Surg 57:86–88

    Article  PubMed  CAS  Google Scholar 

  • Yokote K, Honjo S, Kobayashi K, Fujimoto M, Kawamura H, Mori S, Saito Y (2004) Metabolic improvement and abdominal fat redistribution in Werner syndrome by pioglitazone. J Am Geriatr Soc 52:1582–1583

    Article  PubMed  Google Scholar 

  • Yu CE, Oshima J, Wijsman EM, Nakura J, Miki T, Piussan C, Matthews S, Fu YH, Mulligan J, Martin GM, Schellenberg GD (1997) Mutations in the consensus helicase domains of the Werner syndrome gene. Werner’s Syndrome Collaborative Group. Am J Hum Genet 60:330–341

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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).

Author information

Authors and Affiliations

  1. Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Dr, Baltimore, MD, 21224, USA

    Meltem Muftuoglu & Vilhelm A. Bohr

  2. Department of Pathology, University of Washington, Seattle, WA, 98195, USA

    Junko Oshima & Dru F. Leistritz

  3. Cancer Vaccines Group, Chimera Pharma (Bionostra Group), 28760 Tres Cantos, Madrid, Spain

    Cayetano von Kobbe

  4. Department of Nutrition and Food Science, University of Maryland, College Park, MD, 20742, USA

    Wen-Hsing Cheng

Authors
  1. Meltem Muftuoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junko Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cayetano von Kobbe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Hsing Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dru F. Leistritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vilhelm A. Bohr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vilhelm A. Bohr.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muftuoglu, M., Oshima, J., von Kobbe, C. et al. The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet 124, 369–377 (2008). https://doi.org/10.1007/s00439-008-0562-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-008-0562-0

Keywords

Search

Navigation