Abstract
Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.
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References
Brosh RM Jr, Opresko PL, Bohr VA (2006) Enzymatic mechanism of the WRN helicase/nuclease. Methods Enzymol 409:52–85
Buratti E, Baralle M, Baralle FE (2006) Defective splicing, disease and therapy: searching for master checkpoints in exon definition. Nucleic Acids Res 34:3494–3510
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
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
Goto M (1997) Hierarchical deterioration of body systems in Werner’s syndrome: implications for normal ageing. Mech Ageing Dev 98:239–254
Goto M, Matsuura M (2008) Secular trends towards delayed onsets of pathologies and prolonged longevities in Japanese patients with Werner syndrome. Biosci Trends 2:81–87
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
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
Gray MD, Shen JC, Kamath-Loeb AS, Blank A, Sopher BL, Martin GM, Oshima J, Loeb LA (1997) The Werner syndrome protein is a DNA helicase. Nat Genet 17:100–103
Gu W, Zhang F, Lupski JR (2008) Mechanisms for human genomic rearrangements. Pathogenetics 1:4
Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10:551–564
Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD et al (1992) Identification of heregulin, a specific activator of p185erbB2. Science 256:1205–1210
Huang S, Li B, Gray MD, Oshima J, Mian IS, Campisi J (1998) The premature ageing syndrome protein, WRN, is a 3′ → 5′ exonuclease. Nat Genet 20:114–116
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 Herbay A, 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
Kitano K, Kim SY, Hakoshima T (2010) Structural basis for DNA strand separation by the unconventional winged-helix domain of RecQ helicase WRN. Structure 18:177–187
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081
Leistritz DF, Hanson NB, Martin GM, Oshima J (2007) Werner syndrome. In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997–2010. http://www.genetests.org
Martin GM (1978) Genetic syndromes in man with potential relevance to the pathobiology of aging. Birth Defects Orig Artic Ser 14:5–39
Martin GM, Oshima J (2000) Lessons from human progeroid syndromes. Nature 408:263–266
Masala MV, Scapaticci S, Olivieri C, Pirodda C, Montesu MA, Cuccuru MA, Pruneddu S, Danesino C, Cerimele D (2007) Epidemiology and clinical aspects of Werner’s syndrome in North Sardinia: description of a cluster. Eur J Dermatol 17:213–216
Matsumoto T, Imamura O, Yamabe Y, Kuromitsu J, Tokutake Y, Shimamoto A, Suzuki N, Satoh M, Kitao S, Ichikawa K, Kataoka H, Sugawara K, Thomas W, Mason B, Tsuchihashi Z, Drayna D, Sugawara M, Sugimoto M, Furuichi Y, Goto M (1997) Mutation and haplotype analyses of the Werner’s syndrome gene based on its genomic structure: genetic epidemiology in the Japanese population. Hum Genet 100:123–130
Matsumoto T, Imamura O, Goto M, Furuichi Y (1998) Characterization of the nuclear localization signal in the DNA helicase involved in Werner’s syndrome. Int J Mol Med 1:71–76
Muftuoglu M, Kulikowicz T, Beck G, Lee JW, Piotrowski J, Bohr VA (2008a) Intrinsic ssDNA annealing activity in the C-terminal region of WRN. Biochemistry 47:10247–10254
Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA (2008b) The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet 124:369–377
Nakura J, Wijsman EM, Miki T, Kamino K, Yu CE, Oshima J, Fukuchi K, Weber JL, Piussan C, Melaragno MI et al (1994) Homozygosity mapping of the Werner syndrome locus (WRN). Genomics 23:600–608
Opresko PL (2008) Telomere ResQue and preservation—roles for the Werner syndrome protein and other RecQ helicases. Mech Ageing Dev 129:79–90
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
Oshima J, Magner DB, Lee JA, Breman AM, Schmitt ES, White LD, Crowe CA, Merrill M, Jayakar P, Rajadhyaksha A, Eng CM, del Gaudio D (2009) Regional genomic instability predisposes to complex dystrophin gene rearrangements. Hum Genet 126:411–423
Pagani F, Baralle FE (2004) Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389–396
Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900
Satoh M, Imai M, Sugimoto M, Goto M, Furuichi Y (1999) Prevalence of Werner’s syndrome heterozygotes in Japan. Lancet 353:1766
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892
Suzuki T, Shiratori M, Furuichi Y, Matsumoto T (2001) Diverged nuclear localization of Werner helicase in human and mouse cells. Oncogene 20:2551–2558
Tan W, Wang Y, Gold B, Chen J, Dean M, Harrison PJ, Weinberger DR, Law AJ (2007) Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. J Biol Chem 282:24343–24351
Uhrhammer NA, Lafarge L, Dos Santos L, 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
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262
Zlotogora J (2007) Multiple mutations responsible for frequent genetic diseases in isolated populations. Eur J Hum Genet 15:272–278
Acknowledgments
We thank Ms. Mizue Kishida for her assistance in curating the mutations. This work was supported by R24CA78088 (Martin), R21AG033313 (Oshima), the Ellison Medical Foundation Senior Scholar Award (Oshima), and the German Research Foundation (DFG) in the framework of the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (Kubisch).
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Friedrich, K., Lee, L., Leistritz, D.F. et al. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet 128, 103–111 (2010). https://doi.org/10.1007/s00439-010-0832-5
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DOI: https://doi.org/10.1007/s00439-010-0832-5