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Werner syndrome

Written2000-10Mounira Amor-Guéret
Institut Curie - Section de Recherche, UMR 2027 CNRS, Bâtiment 110, Centre Universitaire, F-91405 Orsay Cedex, France

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Identity

Atlas_Id 10017
Genes implicated inWRN  
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

    Bibliography

    Ku complex interacts with and stimulates the Werner protein.
    Cooper MP, Machwe A, Orren DK, Brosh RM, Ramsden D, Bohr VA
    Genes & development. 2000 ; 14 (8) : 907-912.
    PMID 10783163
     
    The gene responsible for Werner syndrome may be a cell division counting gene.
    Faragher RG, Kill IR, Hunter JA, Pope FM, Tannock C, Shall S
    Proceedings of the National Academy of Sciences of the United States of America. 1993 ; 90 (24) : 12030-12034.
    PMID 8265666
     
    Mutator phenotype of Werner syndrome is characterized by extensive deletions.
    Fukuchi K, Martin GM, Monnat RJ Jr
    Proceedings of the National Academy of Sciences of the United States of America. 1989 ; 86 (15) : 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
    Human genetics. 1990 ; 84 (3) : 249-252.
    PMID 2303247
     
    Variegated translocation mosaicism in human skin fibroblast cultures.
    Hoehn H, Bryant EM, Au K, Norwood TH, Boman H, Martin GM
    Cytogenetics and cell genetics. 1975 ; 15 (5) : 282-298.
    PMID 1222585
     
    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 (6) : 1345-1352.
    PMID 10189141
     
    Functional interaction between the Werner Syndrome protein and DNA polymerase delta.
    Kamath-Loeb AS, Johansson E, Burgers PM, Loeb LA
    Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (9) : 4603-4608.
    PMID 10781066
     
    Functional interaction between Ku and the werner syndrome protein in DNA end processing.
    Li B, Comai L
    The Journal of biological chemistry. 2000 ; 275 (37) : 28349-28352.
    PMID 10880505
     
    Nucleolar localization of the Werner syndrome protein in human cells.
    Marciniak RA, Lombard DB, Johnson FB, Guarente L
    Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (12) : 6887-6892.
    PMID 9618508
     
    WRN mutations in Werner syndrome.
    Moser MJ, Oshima J, Monnat RJ Jr
    Human mutation. 1999 ; 13 (4) : 271-279.
    PMID 10220139
     
    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
    Human genetics. 1997 ; 101 (2) : 121-125.
    PMID 9402954
     
    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 M, Melaragno MI, Fraccaro M, Scappaticci S, Matthews J, Ouais S, Jarzebowicz A, Schellenberg GD, Martin GM
    Human molecular genetics. 1996 ; 5 (12) : 1909-1913.
    PMID 8968742
     
    Werner syndrome and biological ageing: a molecular genetic hypothesis.
    Thweatt R, Goldstein S
    BioEssays : news and reviews in molecular, cellular and developmental biology. 1993 ; 15 (6) : 421-426.
    PMID 8357345
     
    Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.
    Wyllie FS, Jones CJ, Skinner JW, Haughton MF, Wallis C, Wynford-Thomas D, Faragher RG, Kipling D
    Nature genetics. 2000 ; 24 (1) : 16-17.
    PMID 10615119
     
    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, Ouais S, Martin GM, Mulligan J, Schellenberg GD
    Science (New York, N.Y.). 1996 ; 272 (5259) : 258-262.
    PMID 8602509
     

    Citation

    This paper should be referenced as such :
    Amor-Guéret, M
    Werner syndrome
    Atlas Genet Cytogenet Oncol Haematol. 2000;4(4):224-225.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Tumors/WernerID10017.html


    External links

    OMIM277700
    OrphanetWerner syndrome
    MeSHD014898  
    MedGenD014898  
    UMLSC0043119  
    ICD-10E34.8  
    HGMD128446
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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