Werner syndrome

Identity

Atlas_Id	10017
Genes implicated in	WRN
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 Name	WRN
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

OMIM	277700
Orphanet	Werner syndrome
MeSH	D014898
MedGen	D014898
UMLS	C0043119
ICD-10	E34.8
HGMD	128446

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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