Cancer prone diseases
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Autosomal recessive; prevalence of carriers is as high as 1 in 150 to 1 in 200; frequency is about 0.3\/10
5 newborns in Japanese
902 Werner syndrome
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
Malignancy is found in approximately 10% of WRN patients
Excess of soft-tissue sarcomas,
, myeloid disorders and benign meningiomas. In addition, the Japanese have an excess of melanomas and follicular, and anaplastic thyroid carcinomas
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
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.
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
no complementation group
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
nuclear, predominant nucleolar localization
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
with the RecQ helicases
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
Ku complex interacts with and stimulates the Werner protein.
Cooper MP et al
The gene responsible for Werner syndrome may be a cell division "counting" gene.
Faragher RG et al
Mutator phenotype of Werner syndrome is characterized by extensive deletions.
Fukuchi K et al
Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients.
Fukuchi K et al
Variegated translocation mosaicism in human skin fibroblast cultures.
Hoehn H et al
Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race.
Ishikawa Y et al
Functional interaction between the Werner Syndrome protein and DNA polymerase delta.
Kamath-Loeb AS et al
Functional interaction between Ku and the werner syndrome protein in DNA end processing.
Li B et al
Nucleolar localization of the Werner syndrome protein in human cells.
Marciniak RA et al
WRN mutations in Werner syndrome.
Moser MJ et al
An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants.
Ogburn CE et al
Homozygous and compound heterozygous mutations at the Werner syndrome locus.
Oshima J et al
Werner syndrome and biological ageing: a molecular genetic hypothesis.
Thweatt R et al
Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.
Wyllie FS et al
Positional cloning of the Werner's syndrome gene.
Yu CE et al
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