Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Werner syndrome

Identity

Inheritance Autosomal recessive; prevalence of carriers is as high as 1 in 150 to 1 in 200; frequency is about 0.3/105 newborns in Japanese

Clinics

Note Uncommon disorder characterized by early onset of geriatric diseases and described as a "caricature of aging" or "progeria of adults"
Phenotype and clinics Early onset of atherosclerosis, osteoporosis, diabetes mellitus, scleroderma-like skin changes, especially in the extremities, cataract, graying of the hair, subcutaneous calcification, slender limbs, stocky trunk, beaked nose and cancers of non-epithelial cell origin
Neoplastic risk
  • Malignancy is found in approximately 10% of WRN patients
  • Excess of soft-tissue sarcomas, osteosarcomas, myeloid disorders and benign meningiomas. In addition, the Japanese have an excess of melanomas and follicular, and anaplastic thyroid carcinomas
    • Evolution
  • During the first decade of life, WS patients appear normal: the first manifestation is lack of the adolescent growth spurt
  • In the twenties, WS patients develop bilateral ocular cataract and premature graying of the hair
  • In the thirties and forties, osteoporosis, type II diabete mellitus, accelerated atherosclerosis, and cancer occur
  • In the fourth and fifth decades, WS patients often succumb to cardiovascular disease or cancer

    • Cytogenetics

    Inborn conditions 'Variegated translocation mosaicism' : skin fibroblast cell lines from WRN patients are usually composed of one or several clones, each marked by a distinctive, apparently balanced translocation.

    Other findings

    Note
  • WS cells express constitutively high levels of collagenase in vitro.
  • WS cells exhibit a mutator phenotype characterized by extensive deletions: 8-fold higher average frequency of 6-thioguanine-resistant lymphocytes in Werner syndrome patients than in sex- and age-matched normal controls
  • WS cells usually achieve only about 20 population doublings versus approximately 60 in normal cells in culture (WRN gene could be a 'counting' gene controlling the number of times that human cells are able to divide before terminal differentiation). Forced expression of telomerase in Werner syndrome fibroblasts confers extended cellular life span and probable immortality.

    • Genes involved and Proteins

    Complementation groups no complementation group
     
    Gene NameWRN
    Location 8p12
    Protein
    Description 1432 amino acids; contains one ATP binding site, one DEXH helicase box, one exonuclease domain unique among known RecQ helicases in the N-terminal region, a nuclear localization signal in the C-terminus and a direct repeat of 27 amino acids between the exonuclease and helicase domains
    Localisation nuclear, predominant nucleolar localization
    Function 3'-5' DNA helicase; 3'-5' exonuclease; functionally interacts with DNA polymerase delta (POLD1), which is required for DNA replication and DNA repair; functionally interacts with Ku, involved in double strand DNA break repair by non-homologous DNA end joining
    Homology with the RecQ helicases
    Mutations
    Germinal All of the WRN mutations found to date either create a stop codon or cause frameshifts that lead to premature termination: not a single missense mutation had been identified

    External links

    GeneCardsWRN
    GDBWRN
    LocusLinkWRN
    GenBankL76937 [ SRS ]    L76937 [ ENTREZ]
    UnigeneHs.150477 [ SRS ]    Hs.150477 [ NCBI ]
    SwissProtWRN_HUMAN [ SRS ]    WRN_HUMAN [ EXPASY ]
    OMIM277700
    OrphanetWerner syndrome
    HGMD128446
    Other databasehttp://www.ncbi.nlm.nih.gov/cgi-bin/SCIENCE96/gene?WRN

    Bibliography

    Variegated translocation mosaicism in human skin fibroblast cultures.
    Hoehn H, Bryant EM, Au K; Norwood TH, Boman H, Martin GM.
    Cytogenet Cell Genet 1975; 15: 282-298.
    PMID 1222585
     
    Mutator phenotype of Werner syndrome is characterized by extensive deletions.
    Fukuchi K, Martin GM, Monnat RJ Jr.
    Proc Nat Acad Sci 1989; 86: 5893-5897.
    PMID 2762303
     
    Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients.
    Fukuchi K, Tanaka K, Kumahara Y, Marumo K, Pride MB, Martin GM, Monnat RJ Jr.
    Hum Genet 1990; 84: 249-252.
    PMID 2303247
     
    The gene responsible for Werner syndrome may be a cell division 'counting' gene.
    Faragher RGA, Kill IR, Hunter JAA, Pope FM, Tannock C, Shall S.
    Proc Nat Acad. Sci 1993; 90:12030-12034.
    PMID 8265666
     
    Werner syndrome and biological ageing: a molecular genetic hypothesis.
    Thweatt R, Goldstein S.
    BioEssays 1993; 15: 421-426.
    PMID 8357345
     
    Homozygous and compound heterozygous mutations at the Werner syndrome locus.
    Oshima J, Yu CE, Piussan C, Klein G, Jabkowski J, Balci S, Miki T, Nakura J, Ogihara T, Ells J, Smith MAC, Melaragno MI, Fraccaro M, Scappaticci S, Matthews J, Ouais S, Jarzebowicz A, Schellenberg GD, Martin GM.
    Hum Molec Genet 1996; 5: 1909-1913.
    PMID 8968742
     
    Positional cloning of the Werner's syndrome gene.
    Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Quais S, Martin GM, Mulligan J, Schellenberg GD.
    Science 1996; 272: 258-262.
    PMID 8602509
     
    An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants.
    Ogburn CE, Oshima J, Poot M, Chen R, Hunt KE, Gollahon KA, Rabinovitch PS, Martin GM.
    Hum Genet 1997; 101: 121-125.
    PMID 9402954
     
    Nucleolar localization of the Werner syndrome protein in human cells.
    Marciniak RA Lombard DB, Johnson FB, Guarente L.
    Proc Nat Acad Sci 1998; 95: 6887-6892.
    PMID 9618508
     
    Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race.
    Ishikawa Y, Sugano H, Matsumoto T, Furuichi Y, Miller RW, Goto M.
    Cancer 1999; 85: 1345-1352.
    PMID 99203224
     
    WRN mutations in Werner syndrome.
    Moser MJ, Oshima J, Monnat RJ Jr.
    Hum Mutat 1999; 13: 271-279.
    PMID 10220139
     
    Functional interaction between the Werner syndrome protein and DNA polymerase delta.
    Kamath-Loeb AS, Johansson E, Burgers PMJ, Loeb LA.
    Proc Nat Acad Sci 2000; 97: 4603-4608.
    PMID 10781066
     
    Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.
    Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C, Wynford-Thomas D, Faragher RGA, Kipling D.
    Nature Genet 2000; 24: 16-17.
    PMID 10615119
     
    Ku complex interacts with and stimulates the Werner protein.
    Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D, Bohr VA.
    Genes Dev. 2000;14: 907-912.
     
    Functional interaction between Ku and the werner syndrome protein in DNA end processing.
    Li B, Comai L.
    J Biol Chem. 2000; 275: 28349-28352.
    PMID 20435782
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Contributor(s)

    Written10-2000Mounira Amor-Guéret

    Citation

    This paper should be referenced as such :
    Amor-Guéret M . Werner syndrome. Atlas Genet Cytogenet Oncol Haematol. October 2000 .
    URL : http://AtlasGeneticsOncology.org/Kprones/WernerID10017.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Thu Apr 17 14:14:12 2008

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