Werner syndrome

2000-10-01   Mounira Amor-Guéret  

Identity

Name

Werner syndrome

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

Omim

277700

Mesh

D014898

Orphanet

902 Werner syndrome

Umls

C0043119

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 condition

    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

    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

    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

    To be noted

    Hgmd

    128446 WRN

    Bibliography

    Pubmed IDLast YearTitleAuthors
    107831632000Ku complex interacts with and stimulates the Werner protein.Cooper MP et al
    82656661993The gene responsible for Werner syndrome may be a cell division "counting" gene.Faragher RG et al
    27623031989Mutator phenotype of Werner syndrome is characterized by extensive deletions.Fukuchi K et al
    23032471990Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients.Fukuchi K et al
    12225851975Variegated translocation mosaicism in human skin fibroblast cultures.Hoehn H et al
    101891411999Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race.Ishikawa Y et al
    107810662000Functional interaction between the Werner Syndrome protein and DNA polymerase delta.Kamath-Loeb AS et al
    108805052000Functional interaction between Ku and the werner syndrome protein in DNA end processing.Li B et al
    96185081998Nucleolar localization of the Werner syndrome protein in human cells.Marciniak RA et al
    102201391999WRN mutations in Werner syndrome.Moser MJ et al
    94029541997An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants.Ogburn CE et al
    89687421996Homozygous and compound heterozygous mutations at the Werner syndrome locus.Oshima J et al
    83573451993Werner syndrome and biological ageing: a molecular genetic hypothesis.Thweatt R et al
    106151192000Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.Wyllie FS et al
    86025091996Positional cloning of the Werner's syndrome gene.Yu CE et al