SNOMEDCT: 51626007; ORPHA: 902; DO: 5688;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p12 | Werner syndrome | 277700 | Autosomal recessive | 3 | RECQL2 | 604611 |
A number sign (#) is used with this entry because Werner syndrome (WRN) is caused by homozygous or compound heterozygous mutation in the RECQL2 gene (604611), which encodes a homolog of the E. coli RecQ DNA helicase, on chromosome 8p12.
See also Hutchinson-Gilford progeria syndrome (HGPS; 176670), a more severe progeroid syndrome with earlier onset caused by mutation in the LMNA gene (150330).
Werner syndrome (WRN) is a rare autosomal recessive segmental progeroid syndrome. Patients exhibit not only an appearance of accelerated aging (premature graying, thinning of hair, skin atrophy and atrophy of subcutaneous fat), but also several disorders commonly associated with aging, including bilateral cataracts, diabetes mellitus, osteoporosis, premature arteriosclerosis, and a variety of benign and malignant neoplasms (summary by Oshima et al., 1996).
The features of Werner syndrome are scleroderma-like skin changes, especially in the extremities, cataract, subcutaneous calcification, premature arteriosclerosis, diabetes mellitus, and a wizened and prematurely aged facies. A particularly instructive pedigree was reported by McKusick (1963). The habitus is characteristic, with short stature, slender limbs, and stocky trunk. The nose is beaked.
Epstein et al. (1966) studied a Japanese patient living in Seattle. Goto et al. (1981) studied 42 Japanese families containing 80 affected persons. Autosomal recessive inheritance was confirmed. Malignancy was frequent in the patients and in the families generally. HLA was not linked. The frequency of Werner syndrome in Japan was estimated to be about 3 per million persons. The origin of the grandparents of the cases would be of interest.
Ruprecht (1989) reported that in 10 of 18 eyes from 9 patients with Werner syndrome, cataract surgery was complicated by wound dehiscence and its consequences. Additionally, corneal endothelial decompensation occurred in 8 eyes. In view of the reduced growth potential of fibroblasts, he suggested small surgical incisions and other modifications of the usual procedures of cataract surgery, including no local or systemic use of cortisone.
Khraishi et al. (1992) described a 47-year-old woman with WRN who had been misdiagnosed as having progressive systemic sclerosis with metastatic calcification for 12 years and then developed a painful, distal femoral, osteoblastic cortical juxtaarticular lesion with exuberant soft tissue calcification. This lesion proved to be an osteosarcoma requiring amputation.
Goto et al. (1996) found in the literature 124 case reports of neoplasia and Werner syndrome from Japan and 34 case reports from outside Japan, from 1939 to 1995. They found a greater diversity of neoplasia in WRN than was previously known. In Japanese, there were 127 cancers, 14 benign meningiomas, and 5 myeloid disorders, as compared with 30 cancers, 7 benign meningiomas, and 2 myeloid disorders, in non-Japanese. The ratio of epithelial to nonepithelial cancers was about 1:1 for Japanese and for non-Japanese, instead of the usual 10:1. Both series had excesses of soft tissue sarcoma (STS), osteosarcoma, myeloid disorders, and benign meningioma. In addition, the Japanese had an excess of thyroid cancer and melanoma, including 5 intranasal and 13 foot. STS, osteosarcoma, melanoma, and thyroid carcinoma accounted for 57% of all cancer in WRN as compared with an expected 2%, based on the Osaka population between 25 and 64 years of age. Multiple tumors were reported in 19 Japanese and 5 non-Japanese. In Japan, 9 first-degree relatives had WRN and cancer, 6 of whom were concordant as to site and/or cell type.
Martin (1997) gave a thoughtful review of the question of whether the Werner mutation is a bona fide reflection of mechanisms of 'normal aging.'
Mohaghegh and Hickson (2001) reviewed the DNA helicase deficiencies associated with cancer predisposition and premature aging disorders.
Chromosomal Instability in Werner Syndrome
'Variegated translocation mosaicism' was the designation proposed by W. W. Nichols (Hoehn et al., 1975) for a phenomenon he and others observed in cells from patients with Werner syndrome: skin fibroblast cell lines were usually composed of one or several clones, each marked by a distinctive, apparently balanced translocation. Salk (1982) found that somatic cells from Werner syndrome patients reveal a propensity to develop chromosomal aberrations, including translocations, inversions, and deletions. In fibroblast cell lines and lymphoblastoid cell lines made from circulating B lymphocytes in 2 brothers born of first-cousin parents, Schonberg et al. (1984) demonstrated variegated translocation mosaicism as well as the abbreviated life span characteristic of cell lines from these patients.
In studies with clastogens, Gebhart et al. (1988) concluded that Werner syndrome cells demonstrate some biochemical differences that distinguishing them from those of other classic chromosome instability syndromes.
Fukuchi et al. (1989) demonstrated increased frequency of chromosomal deletions in cell lines from patients with WRN. Scappaticci et al. (1990) found multiple numerical and structural chromosomal abnormalities in cultured lymphocytes of 4 patients with Werner syndrome; several of the changes were clonal.
Fukuchi et al. (1990) found an 8-fold higher average frequency of 6-thioguanine-resistant lymphocytes in Werner syndrome patients compared to normal controls, suggesting there were increased spontaneous chromosome rearrangements and deletions in WRN cells consistent with a human genomic instability or 'mutator' syndrome. Monnat et al. (1992) determined the junction region sequences of deletions in the HPRT gene (308000) from thioguanine-resistant Werner syndrome fibroblasts. Given the potential for homologous recombination between copies of repeated DNA sequences that constitute approximately a third of the human HPRT gene, they were surprised to discover that all the deletions were generated by nonhomologous recombination of donor DNA duplexes that share little nucleotide sequence identity. No difference in structure or complexity was observed between deletions isolated from Werner syndrome fibroblasts or from myeloid leukemia cells. This suggested to Monnat et al. (1992) that the Werner syndrome deletion mutator uses deletion mutagenesis pathways that are similar or identical to those used in other human somatic cells.
Ogburn et al. (1997) found that immortalized B lymphocytes from individuals with Werner syndrome were hypersensitive to 4-nitro-quinoline-1-oxide (4NQO), supporting earlier work on T lymphocytes. They also showed that B cell lines from clinically normal heterozygous carriers, with approximately 50% residual helicase activity, exhibited intermediate sensitivities to this genotoxic agent. Since the prevalence of carriers is as high as 1 in 150 to 1 in 200, Ogburn et al. (1997) suggested that a deleterious phenotype associated with a carrier state could have potential public health concern. Moser et al. (2000) used the glycophorin A (GPA) somatic cell mutation assay (Jensen and Bigbee, 1996) to analyze genetic instability in vivo in WRN patients and heterozygotes. GPA variant frequencies were determined for 11 patients and 10 heterozygous family members who collectively carried 10 different WRN mutations. An increase in variant frequency was strongly age-dependent in WRN patients. Allele loss variants were also significantly elevated in heterozygous family members, thus providing the first evidence for in vivo genetic instability in heterozygous carriers in an autosomal recessive genetic instability syndrome.
Prince et al. (1999) showed that Werner syndrome fibroblast cell lines are unusually sensitive to the DNA-damaging agent 4NQO, although not to gamma radiation or to hydrogen peroxide. The fusion of 4NQO-sensitive WRN and 4NQO-resistant control fibroblast cell lines generated proliferating cell hybrids that expressed WRN protein and were 4NQO-resistant. These results established the recessive nature of 4NQO sensitivity in WRN cell lines and provided a cellular assay for WRN protein function.
Crabbe et al. (2007) demonstrated that replication-associated telomere loss was responsible for chromosome fusions found in Werner syndrome fibroblasts. Using metaphase analysis, the authors showed that telomere elongation by telomerase (TERT; 187270) significantly reduced the appearance of new chromosomal aberrations in cells lacking the WRN helicase, similar to complementation of Werner syndrome cells with the WRN helicase. Crabbe et al. (2007) proposed a mechanism in which lack of WRN helicase activity results in dramatic telomere loss from individual sister chromatids, causing a DNA damage and repair response that leads to chromosome fusion-breakage cycles and genomic instability. The findings suggested that genome instability in Werner syndrome cells, which may lead to cancer, depends directly on telomere dysfunction.
Bauer et al. (1986) found that fibroblasts from a patient with Werner syndrome had a markedly attenuated mitogenic response to platelet-derived growth factor (PDGF; see 190040) and fibroblast growth factor (FGF; see 131220) despite normal cellular growth factor binding and receptors. The findings suggested that a defect in growth factor-mediated pathways may contribute to the WRN phenotype.
The finite replicative life span of human cells in vitro, the Hayflick phenomenon (Hayflick, 1965), is due to the stochastic loss of replicative ability in a continuously increasing fraction of newborn cells at every generation. Normal human fibroblasts achieve approximately 60 population doublings in culture, while Werner syndrome cells usually achieve only about 20 population doublings. There are 2 alternative kinetic explanations for the decreased life span of Werner syndrome cells. First, the initial fraction of cycling cells in a fresh explant may be approximately the same as in an explant derived from a normal subject, but the rate of loss of reproductive ability may be much higher in Werner syndrome cells. Second, when freshly explanted, the Werner syndrome cells may contain a much smaller fraction of cycling cells, which lose their reproductive ability at a normal rate. Of course, a combination of the 2 mechanisms is possible. To distinguish between the 2 main hypotheses, Faragher et al. (1993) studied cells from an obligate heterozygote, determining the fraction of cells in S phase throughout the life span of cultures. They found that the cells in these cultures usually exited, apparently irreversibly, from the cell cycle at a faster rate than did normal cells, although for the most part they started off with good replicative ability. They proposed that the Werner syndrome gene is a 'counting' gene controlling the number of times that human cells are able to divide before terminal differentiation. Thweatt and Goldstein (1993) arrived at a similar hypothesis. They pointed out that several overexpressed gene sequences isolated from a Werner syndrome fibroblast cDNA library possessed the capacity to inhibit DNA synthesis and disrupt many normal biochemical processes. Because a similar constellation of genes is overexpressed in senescent normal fibroblasts, the findings suggested a common molecular genetic pathway for replicative senescence in the 2 types of cells. Thweatt and Goldstein (1993) proposed that the primary defect in WRN is a mutation in a gene for a trans-acting repressor protein that reduces its binding affinity for shared regulatory regions of several genes, including those that encode inhibitors of DNA synthesis. The mutant WRN repressor gene triggers a sequence of premature expression of inhibitors of DNA synthesis and other genes, with resulting inhibition of DNA synthesis and early cellular senescence, events that occur much later in normal cells.
Matsumoto et al. (1997) presented evidence that the helicase that is defective in Werner syndrome is missing the nuclear localization signal (NLS) and that this leads to impaired nuclear import as a major contributing factor in the molecular pathology of the disorder. The finding helped to explain the enigma that most Werner syndrome patients have similar clinical phenotypes no matter how different their mutations. The role the Werner syndrome helicase plays in the nucleus in preventing premature aging remained to be clarified.
Wyllie et al. (2000) showed that forced expression of telomerase (187270) in Werner syndrome fibroblasts conferred extended cellular life span and probable immortality. Telomerase activity and telomere extension was is sufficient to prevent premature senescence of Werner syndrome fibroblast cultures. The findings suggested that one consequence of the Werner syndrome defect is an acceleration of normal telomere-driven replicative senescence, and suggested a route to therapeutic intervention in this human progeroid syndrome.
Krejci et al. (2003) clarified the role of Srs2 in recombination modulation by purifying its encoded product and examining its interactions with the RAD51 recombinase (179617). Srs2 has a robust ATPase activity that is dependent on single-stranded DNA and binds RAD51, but the addition of a catalytic quantity of Srs2 to RAD51-mediated recombination reactions causes severe inhibition of these reactions. Krejci et al. (2003) showed that Srs2 acts by dislodging RAD51 from single-stranded DNA. Thus, the attenuation of recombination efficiency by Srs2 stems primarily from its ability to dismantle the RAD51 presynaptic filament efficiently. Krejci et al. (2003) suggested that their findings have implications for the basis of Bloom (210900) and Werner syndromes, which are caused by mutations in DNA helicases and are characterized by increased frequencies of recombination and a predisposition to cancers and accelerated aging.
Baird et al. (2004) showed that the mean rate of telomere shortening in WRN bulk cultures ranged between that of normal fibroblasts (99 bp/population doubling) and 4 times that of normal (355 bp/population doubling). Telomere erosion rates in clones of WRN cells were much reduced compared with bulk cultures, as were the variances of the telomere length distributions. The overall lack of length heterogeneity and the normal erosion rates of the clonal populations were consistent with simple end-replication losses as the major contributor to telomere erosion in WRN cells. The authors proposed that telomere dynamics at the single-cell level in WRN fibroblasts are not significantly different from those in normal fibroblasts, and suggested that the accelerated replicative decline seen in WRN fibroblasts may not result from accelerated telomere erosion.
Because insulin resistance in Werner syndrome may be due to defective signaling distal to the insulin receptor (147670), Izumino et al. (1997) analyzed the metabolic effects of troglitazone, an antidiabetic drug that sensitizes insulin action, in 5 patients with Werner syndrome. Each patient was treated with 400 mg/day of troglitazone for 4 weeks and underwent a 75-g oral glucose tolerance test (OGTT) and frequently sampled iv glucose tolerance tests. Treatment reduced the area under the curve of glucose and insulin in the OGTT by 26% and 43%, respectively. Glucose tolerance, expressed as the glucose disappearance rate, improved significantly (1.36 +/- 0.16 to 1.94 +/- 0.30%/min; P less than 0.005). The authors found that troglitazone ameliorates glucose intolerance mediated by increased insulin sensitivity as well as glucose effectiveness, as assessed by minimal analysis, in Werner syndrome patients.
In a study of 21 Japanese families originating in 16 different prefectures, Goto et al. (1992) did linkage studies demonstrating close linkage of WRN to a group of markers on chromosome 8. At least 3 of the 4 following major signs were required for the diagnosis: characteristic habitus and stature, premature senescence, scleroderma-like skin changes, and endocrine abnormalities. The first suggestion of linkage was increased homozygosity for ankyrin (ANK1; 612641) and D8S87. The ANK1 locus is located at 8p11.2. The Werner syndrome showed a maximum lod score of 2.89 at theta = 0.058 for linkage with ANK1. A multipoint lod score of 9.92 was obtained for the linkage of Werner syndrome with 3 markers. No linkage was found with lipoprotein lipase (238600), and other evidence suggested that this locus lies closer to 8pter than does the Werner syndrome locus. A likely location for the WRN gene appeared to be 8p12-p11. Schellenberg et al. (1992) confirmed the assignment by homozygosity mapping, i.e., linkage analysis using affected individuals from first- or second-cousin marriages. A peak lod score of 5.58 at a recombination fraction of 0.03 was obtained with D8S87.
By linkage studies, Thomas et al. (1993) determined that the heregulin locus (142445) is distal to WRN and that ANK1 and PLAT (173370) are in that order on the centromeric side of WRN.
Nakura et al. (1994) studied 27 Werner syndrome kindreds of various ethnic origins, 26 of which were consanguineous. In 24 of these families, the affected subject was given the diagnosis of definite Werner syndrome and affected subjects in the remaining 3 pedigrees were given the diagnosis of probable Werner syndrome. With 2-point linkage analysis using 13 short tandem repeat polymorphic sites on 8p, Nakura et al. (1994) found that the locus yielding a maximum lod score at the smallest recombination fraction was D8S339. Lod scores in excess of 3.0 were obtained with this marker for both Japanese and Caucasian families. Multipoint analysis of the markers yielded a maximum lod score of 17.05 at a distance of approximately 0.6 cM from D8S339. Combined with the analysis of homozygosity in subjects from inbred pedigrees, the data indicated that the WRN locus is between D8S131 and D8S87, in an 8.3-cM interval containing D8S339.
Yu et al. (1994) used linkage disequilibrium in an attempt to narrow down the location of the WRN gene. They found that D8S339 and 2 polymorphisms at the glutathione reductase locus (138300) showed strong statistically significant evidence of disequilibrium with WRN in the Japanese population but not in the Caucasian population. In addition, they showed that a limited number of haplotypes are associated with the disease in both populations and that these haplotypes define clusters of apparently related haplotypes that may identify as many as 8 or 9 independent WRN mutations in these 2 populations.
Ye et al. (1995) used homozygosity mapping with markers derived from an 8p22-p12 microdissection library to type members of Japanese families with WRN. One marker, MS8-134 (D8S1055), showed a lod score of over 20 at theta = 0.00.
Yu et al. (1996) identified 4 mutations in the WRN gene in patients with Werner syndrome. Two of the mutations (604611.0003 and 604611.0004) were splice-junction mutations with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations (604611.0004), which resulted in a frameshift and a predicted truncated protein, was found in the homozygous state in 60% of Japanese Werner syndrome patients examined. The other 2 mutations were nonsense mutations (604611.0001 and 604611.0002). The identification of a mutated putative helicase as the gene product of the WRN gene suggested to Yu et al. (1996) that defective DNA metabolism is involved in a complex process of aging in Werner syndrome patients.
Oshima et al. (1996) reported 9 new WRN mutations in 10 Werner syndrome patients, including 4 Japanese patients and 6 Caucasian patients. These mutations were located at different sites across the coding region. Oshima et al. (1996) noted that all of the WRN mutations found to date either create a stop codon or cause frameshifts that lead to premature terminations. They noted that the WRN protein is partially homologous to RecQ helicases and that it contains 7 helicase motifs, 2 of which have been found in all ATP-binding proteins. Oshima et al. (1996) briefly reviewed the functions of helicases and reported that DNA helicases have been implicated in a number of molecular processes, including unwinding of DNA during replication, DNA repair, and accurate chromosomal segregation.
Goto et al. (1997) studied the helicase gene mutations previously described by Yu et al. (1996) in 89 Japanese Werner syndrome patients. Thirty-five (39.3%) were homozygous for mutation 4 (604611.0004); 1 (1.1%) was homozygous for mutation 1 (604611.0001); 6 (6.7%) were positive for both mutations 1 and 4; 1 was homozygous for a new mutation, which they designated mutation 5 (604611.0005); 13 (14.6%) had a single copy of mutation 4; 3 (3.4%) had a single copy of mutation 1; and the remaining 30 (33.8%) were negative for all 5 mutations. Of the 178 chromosomes in the 89 patients, 89 (50%) carried mutation 4, 11 (6.2%) carried mutation 1, and 2 (1.1%) carried mutation 5. In 76 chromosomes (42.7%), no mutation was identified.
Yu et al. (1997) screened Werner syndrome subjects for mutations and identified 5 new ones. Four of these new mutations either partially disrupted the helicase domain region or resulted in predicted protein products lacking the entire helicase region. Their results confirmed that mutations in the WRN gene are responsible for Werner syndrome. In addition, the location of the mutations indicated that the presence or absence of the helicase domain does not influence the Werner syndrome phenotype, suggesting that this syndrome is the result of complete loss of function of the WRN gene product.
Moser et al. (1999) reviewed the spectrum of WRN mutations in Werner syndrome, the organization and potential functions of the WRN protein, and the possible mechanisms linking the loss of WRN function with the clinical and cellular phenotypes of Werner syndrome.
Monnat (1999) cited results from his own laboratory and from that of the AGENE Research Institute indicating that 80% of the WRN mutations in Japanese Werner syndrome patients led to a lack of detectable mutant protein. Thus many and perhaps all Werner syndrome-associated WRN mutations are likely to be functionally equivalent null alleles. These results contradict the suggestion of Ishikawa et al. (1999) that a different spectrum of mutations in the WRN gene in Japanese may confer a higher risk of thyroid carcinoma of the papillary or follicular type. However, the consistent absence of WRN protein in the cells of patients with Werner syndrome could both favor and partially explain the development of thyroid carcinoma with follicular and anaplastic, as opposed to the more papillary, histology.
Using cDNA microanalysis, Kyng et al. (2003) found that fibroblasts from 4 patients with Werner syndrome and fibroblasts from 5 older control individuals (average age 90 years) showed transcription alteration of 435 (6.3%) of 6,192 genes examined compared to cells from young adult controls. Of the 435 genes, 91% of the 249 genes with known function had similar transcription changes in both Werner syndrome patients and normal old age controls. The major functional categories of the similarly transcribed genes of known function included DNA/RNA metabolism, cell growth, and stress response. Kyng et al. (2003) concluded that Werner syndrome may be a good model for normal aging and that both processes are linked to altered transcription.
Thomas et al. (1993) excluded the FGFR1 gene (136350) as the site of the mutation in Werner syndrome.
In blood samples from Werner syndrome patients, Sadakane et al. (1994) identified large insertions or deletions in the DNA polymerase beta gene (POLB; 174760), which maps to 8p12-p11. A 107-bp insertion was found in 2 independent Werner syndrome patients and in the carrier mother of 1 of the patients, but not in an unaffected sister or in a healthy population. The authors suggested that mutations in the POLB gene may underlie the disorder. However, Chang et al. (1994) presented several lines of evidence suggesting that POLB is not the Werner syndrome gene. Activity gels showed normal enzyme activity and electrophoretic mobility. Nucleotide sequence analysis of the entire coding region failed to demonstrate mutations, although mistakes in the published sequence for POLB were discovered. Single-strand conformation polymorphism (SSCP) and heteroduplex analyses failed to reveal evidence of mutations in the promoter region. A newly discerned polymorphism failed to reveal homozygosity by descent in a consanguineous patient. Fluorescence in situ hybridization placed the POLB gene centromeric to D8S135 at 8p11.2, beyond the region of peak lod scores for Werner syndrome.
Lombard et al. (2000) generated mice bearing a mutation that eliminated expression of the C terminus of the helicase domain of the WRN protein. Mutant mice were born at the expected mendelian frequency and did not show any overt histologic signs of accelerated senescence. The mice were capable of living beyond 2 years of age. Cells from these animals did not show elevated susceptibility to 2 genotoxins. However, mutant fibroblasts aged approximately 1 passage earlier than controls. Importantly, mice that were doubly homozygous for WRN and p53 (191170) deficiencies showed an increased mortality rate relative to animals that were heterozygous for WRN deficiency and homozygous for p53 null. Lombard et al. (2000) considered possible models for the synergy between p53 and WRN mutations for the determination of life span.
Baird, D. M., Davis, T., Rowson, J., Jones, C. J., Kipling, D. Normal telomere erosion rates at the single cell level in Werner syndrome fibroblast cells. Hum. Molec. Genet. 13: 1515-1524, 2004. [PubMed: 15150162] [Full Text: https://doi.org/10.1093/hmg/ddh159]
Bauer, E. A., Silverman, N., Busiek, D. F., Kronberger, A., Deuel, T. F. Diminished response of Werner's syndrome fibroblasts to growth factors PDGF and FGF. Science 234: 1240-1243, 1986. [PubMed: 3022382] [Full Text: https://doi.org/10.1126/science.3022382]
Boyd, M. W. J., Grant, A. P. Werner's syndrome (progeria of the adult): further pathological and biochemical observations. Brit. Med. J. 2: 920-925, 1959. [PubMed: 13803556] [Full Text: https://doi.org/10.1136/bmj.2.5157.920]
Cerimele, D., Cottoni, F., Scappaticci, S., Rabbiosi, G., Borroni, G., Sanna, E., Zei, G., Fraccaro, M. High prevalence of Werner's syndrome in Sardinia: description of six patients and estimate of the gene frequency. Hum. Genet. 62: 25-30, 1982. [PubMed: 7152524] [Full Text: https://doi.org/10.1007/BF00295600]
Chang, M., Burmer, G. C., Sweasy, J., Loeb, L. A., Edelhoff, S., Disteche, C. M., Yu, C.-E., Anderson, L., Oshima, J., Nakura, J., Miki, T., Kamino, K., Ogihara, T., Schellenberg, G. D., Martin, G. M. Evidence against DNA polymerase beta as a candidate gene for Werner syndrome. Hum. Genet. 93: 507-512, 1994. [PubMed: 8168825] [Full Text: https://doi.org/10.1007/BF00202813]
Crabbe, L., Jauch, A., Naeger, C. M., Holtgreve-Grez, H., Karlseder, J. Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc. Nat. Acad. Sci. 104: 2205-2210, 2007. [PubMed: 17284601] [Full Text: https://doi.org/10.1073/pnas.0609410104]
Epstein, C. J., Martin, G. M., Schultz, A. L., Motulsky, A. G. Werner's syndrome: a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine 45: 177-222, 1966. [PubMed: 5327241] [Full Text: https://doi.org/10.1097/00005792-196605000-00001]
Faragher, R. G. A., Kill, I. R., Hunter, J. A. A., Pope, F. M., Tannock, C., Shall, S. The gene responsible for Werner syndrome may be a cell division 'counting' gene. Proc. Nat. Acad. Sci. 90: 12030-12034, 1993. [PubMed: 8265666] [Full Text: https://doi.org/10.1073/pnas.90.24.12030]
Fukuchi, K., Martin, G. M., Monnat, R. J., Jr. Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Nat. Acad. Sci. 86: 5893-5897, 1989. Note: Erratum: Proc. Nat. Acad. Sci. 86: 7994 only, 1989. [PubMed: 2762303] [Full Text: https://doi.org/10.1073/pnas.86.15.5893]
Fukuchi, K., Tanaka, K., Kumahara, Y., Marumo, K., Pride, M. B., Martin, G. M., Monnat, R. J., Jr. Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients. Hum. Genet. 84: 249-252, 1990. [PubMed: 2303247] [Full Text: https://doi.org/10.1007/BF00200569]
Gebhart, E., Bauer, R., Raub, U., Schinzel, M., Ruprecht, K. W., Jonas, J. B. Spontaneous and induced chromosomal instability in Werner syndrome. Hum. Genet. 80: 135-139, 1988. [PubMed: 2459043] [Full Text: https://doi.org/10.1007/BF00702855]
Gebhart, E., Schinzel, M., Ruprecht, K. W. Cytogenetic studies using various clastogens in two patients with Werner syndrome and control individuals. Hum. Genet. 70: 324-327, 1985. [PubMed: 4018799] [Full Text: https://doi.org/10.1007/BF00295370]
Goto, M., Horiuchi, Y., Tanimoto, K., Ishii, T., Nakashima, H. Werner's syndrome: analysis of 15 cases with a review of the Japanese literature. J. Am. Geriat. Soc. 26: 341-347, 1978. [PubMed: 670621] [Full Text: https://doi.org/10.1111/j.1532-5415.1978.tb03681.x]
Goto, M., Imamura, O., Kuromitsu, J., Matsumoto, T., Yamabe, Y., Tokutake, Y., Suzuki, N., Mason, B., Drayna, D., Sugawara, M., Sugimoto, M., Furuichi, Y. Analysis of helicase gene mutations in Japanese Werner's syndrome patients. Hum. Genet. 99: 191-193, 1997. [PubMed: 9048918] [Full Text: https://doi.org/10.1007/s004390050336]
Goto, M., Miller, R. W., Ishikawa, Y., Sugano, H. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol. Biomarkers Prev. 5: 239-246, 1996. [PubMed: 8722214]
Goto, M., Rubenstein, M., Weber, J., Woods, K., Drayna, D. Genetic linkage of Werner's syndrome to five markers on chromosome 8. Nature 355: 735-738, 1992. [PubMed: 1741060] [Full Text: https://doi.org/10.1038/355735a0]
Goto, M., Tanimoto, K., Horiuchi, Y., Sasazuki, T. Family analysis of Werner's syndrome: a survey of 42 Japanese families with a review of the literature. Clin. Genet. 19: 8-15, 1981. [PubMed: 7460386] [Full Text: https://doi.org/10.1111/j.1399-0004.1981.tb00660.x]
Gray, M. D., Shen, J.-C., Kamath-Loeb, A. S., Blank, A., Sopher, B. L., Martin, G. M., Oshima, J., Loeb, L. A. The Werner syndrome protein is a DNA helicase. Nature Genet. 17: 100-103, 1997. [PubMed: 9288107] [Full Text: https://doi.org/10.1038/ng0997-100]
Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37: 614-636, 1965. [PubMed: 14315085] [Full Text: https://doi.org/10.1016/0014-4827(65)90211-9]
Hoehn, H., Bryant, E. M., Au, K., Norwood, T. H., Boman, H., Martin, G. M. Variegated translocation mosaicism in human skin fibroblast cultures. Cytogenet. Cell Genet. 15: 282-298, 1975. [PubMed: 1222585] [Full Text: https://doi.org/10.1159/000130526]
Huang, S., Li, B., Gray, M. D., Oshima, J., Mian, I. S., Campisi, J. The premature ageing syndrome protein, WRN, is a 3-prime-5-prime exonuclease. Nature Genet. 20: 114-116, 1998. [PubMed: 9771700] [Full Text: https://doi.org/10.1038/2410]
Imamura, O., Ichikawa, K., Yamabe, Y., Goto, M., Sugawara, M., Furuichi, Y. Cloning of a mouse homologue of the human Werner syndrome gene and assignment to 8A4 by fluorescence in situ hybridization. Genomics 41: 298-300, 1997. [PubMed: 9143515] [Full Text: https://doi.org/10.1006/geno.1997.4661]
Ishikawa, Y., Sugano, H., Matsumoto, T., Furuichi, Y., Miller, R. W., Goto, M. Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race. Cancer 85: 1345-1352, 1999. [PubMed: 10189141]
Izumino, K., Sakamaki, H., Ishibashi, M., Takino, H., Yamasaki, H., Yamaguchi, Y., Chikuba, N., Matsumoto, K., Akazawa, S., Tokuyama, K., Nagataki, S. Troglitazone ameliorates insulin resistance in patients with Werner's syndrome. J. Clin. Endocr. Metab. 82: 2391-2395, 1997. [PubMed: 9253306] [Full Text: https://doi.org/10.1210/jcem.82.8.4162]
Jensen, R. H., Bigbee, W. L. Direct immunofluorescence labeling provides an improved method for the glycophorin A somatic mutation assay. Cytometry 23: 337-343, 1996. [PubMed: 8900477] [Full Text: https://doi.org/10.1002/(SICI)1097-0320(19960401)23:4<337::AID-CYTO10>3.0.CO;2-U]
Khraishi, M., Howard, B., Little, H. A patient with Werner's syndrome and osteosarcoma presenting as scleroderma. J. Rheum. 19: 810-813, 1992. [PubMed: 1613716]
Krejci, L., Van Komen, S., Li, Y., Villemain, J., Reddy, M. S., Klein, H., Ellenberger, T., Sung, P. DNA helicase Srs2 disrupts the Rad51 presynaptic filament. Nature 423: 305-309, 2003. [PubMed: 12748644] [Full Text: https://doi.org/10.1038/nature01577]
Kyng, K. J., May, A., Kolvraa, S., Bohr, V. A. Gene expression profiling in Werner syndrome closely resembles that of normal aging. Proc. Nat. Acad. Sci. 100: 12259-12264, 2003. [PubMed: 14527998] [Full Text: https://doi.org/10.1073/pnas.2130723100]
Lombard, D. B., Beard, C., Johnson, B., Marciniak, R. A., Dausman, J., Bronson, R., Buhlmann, J. E., Lipman, R., Curry, R., Sharpe, A., Jaenisch, R., Guarente, L. Mutations in the WRN gene in mice accelerate mortality in a p53-null background. Molec. Cell. Biol. 20: 3286-3291, 2000. [PubMed: 10757812] [Full Text: https://doi.org/10.1128/MCB.20.9.3286-3291.2000]
Martin, G. M. The Werner mutation: does it lead to a 'public' or 'private' mechanism of aging? Molec. Med. 3: 356-358, 1997. [PubMed: 9234240]
Matsumoto, T., Shimamoto, A., Goto, M., Furuichi, Y. Impaired nuclear localization of defective DNA helicases in Werner's syndrome. (Letter) Nature Genet. 16: 335-336, 1997. [PubMed: 9241267] [Full Text: https://doi.org/10.1038/ng0897-335]
McKusick, V. A. Medical genetics 1962. J. Chronic Dis. 16: 457-634, 1963. [PubMed: 14042963] [Full Text: https://doi.org/10.1016/0021-9681(63)90148-6]
Meisslitzer, C., Ruppitsch, W., Weirich-Schwaiger, H., Weirich, H. G., Jabkowsky, J., Klein, G., Schweiger, M., Hirsch-Kauffmann, M. Werner syndrome: characterization of mutations in the WRN gene in an affected family. Europ. J. Hum. Genet. 5: 364-370, 1997. [PubMed: 9450180]
Mohaghegh, P., Hickson, I. D. DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum. Molec. Genet. 10: 741-746, 2001. [PubMed: 11257107] [Full Text: https://doi.org/10.1093/hmg/10.7.741]
Monnat, R. J., Jr., Hackmann, A. F. M., Chiaverotti, T. A. Nucleotide sequence analysis of human hypoxanthine phosphoribosyltransferase (HPRT) gene deletions. Genomics 13: 777-787, 1992. [PubMed: 1639404] [Full Text: https://doi.org/10.1016/0888-7543(92)90153-j]
Monnat, R. J., Jr. Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race. (Letter) Cancer 86: 728-729, 1999. [PubMed: 10440702]
Moser, M. J., Bigbee, W. L., Grant, S. G., Emond, M. J., Langlois, R. G., Jensen, R. H., Oshima, J., Monnat, R. J., Jr. Genetic instability and hematologic disease risk in Werner syndrome patients and heterozygotes. Cancer Res. 60: 2492-2496, 2000. [PubMed: 10811130]
Moser, M. J., Oshima, J., Monnat, R. J., Jr. WRN mutations in Werner syndrome. Hum. Mutat. 13: 271-279, 1999. Note: Erratum: Hum. Mutat. 14: 84-85, 1999. [PubMed: 10220139] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<271::AID-HUMU2>3.0.CO;2-Q]
Motulsky, A. G., Schultz, A., Priest, J. H. Werner's syndrome: chromosomes, genes, and the ageing process. Lancet 279: 160-161, 1962. Note: Originally Volume I.
Nakura, J., Wijsman, E. M., Miki, T., Kamino, K., Yu, C.-E., Oshima, J., Fukuchi, K., Weber, J. L., Piussan, C., Melaragno, M. I., Epstein, C. J., Scappaticci, S., Fraccaro, M., Matsumura, T., Murano, S., Yoshida, S., Fujiwara, Y., Saida, T., Ogihara, T., Martin, G. M., Schellenberg, G. D. Homozygosity mapping of the Werner syndrome locus (WRN). Genomics 23: 600-608, 1994. [PubMed: 7851888] [Full Text: https://doi.org/10.1006/geno.1994.1548]
Nordenson, I. Chromosome breaks in Werner's syndrome and their prevention in vitro by radical-scavenging enzymes. Hereditas 87: 151-154, 1977. [PubMed: 608842] [Full Text: https://doi.org/10.1111/j.1601-5223.1978.tb01256.x]
Ogburn, C. E., Oshima, J., Poot, M., Chen, R., Hunt, K. E., Gollahon, K. A., Rabinovitch, P. S., Martin, G. M. An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants. Hum. Genet. 101: 121-125, 1997. [PubMed: 9402954] [Full Text: https://doi.org/10.1007/s004390050599]
Oshima, J., Yu, C.-E., Piussan, C., Klein, G., Jabkowski, J., Balci, S., Miki, T., Nakura, J., Ogihara, T., Ells, J., Smith, M. A. C., Melaragno, M. I., Fraccaro, M., Scappaticci, S., Matthews, J., Ouais, S., Jarzebowicz, A., Schellenberg, G. D., Martin, G. M. Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum. Molec. Genet. 5: 1909-1913, 1996. [PubMed: 8968742] [Full Text: https://doi.org/10.1093/hmg/5.12.1909]
Prince, P. R., Ogburn, C. E., Moser, M. J., Emond, M. J., Martin, G. M., Monnat, R. J., Jr. Cell fusion corrects the 4-nitroquinoline 1-oxide sensitivity of Werner syndrome fibroblast cell lines. Hum. Genet. 105: 132-138, 1999. [PubMed: 10480367] [Full Text: https://doi.org/10.1007/s004399900078]
Rabbiosi, G., Borroni, G. Werner's syndrome: seven cases in one family. Dermatologica 158: 355-360, 1979. [PubMed: 437224] [Full Text: https://doi.org/10.1159/000250780]
Ruprecht, K. W. Ophthalmological aspects in patients with Werner's syndrome. Arch. Gerontol. Geriat. 9: 263-270, 1989. [PubMed: 2640084] [Full Text: https://doi.org/10.1016/0167-4943(89)90045-9]
Sadakane, Y., Maeda, K., Kuroda, Y., Hori, K. Identification of mutations in DNA polymerase beta mRNAs from patients with Werner syndrome. Biochem. Biophys. Res. Commun. 200: 219-225, 1994. [PubMed: 7545922] [Full Text: https://doi.org/10.1006/bbrc.1994.1437]
Salk, D., Au, K., Hoehn, H., Martin, G. M. Effects of radical-scavenging enzymes and reduced oxygen exposure on growth and chromosome abnormalities of Werner syndrome cultured skin fibroblasts. Hum. Genet. 57: 269-275, 1981. [PubMed: 7250969] [Full Text: https://doi.org/10.1007/BF00278942]
Salk, D., Bryant, E., Au, K., Hoehn, H., Martin, G. M. Systematic growth studies, cocultivation, and cell hybridization studies of Werner syndrome cultured skin fibroblasts. Hum. Genet. 58: 310-316, 1981. [PubMed: 7327553] [Full Text: https://doi.org/10.1007/BF00294930]
Salk, D. Werner's syndrome: a review of recent research with an analysis of connective tissue metabolism, growth control of cultured cells, and chromosomal aberrations. Hum. Genet. 62: 1-15, 1982. [PubMed: 6759366] [Full Text: https://doi.org/10.1007/BF00295598]
Samantray, S. K., Samantray, S., Johnson, S. C., Bhaktaviziam, A. Werner syndrome. Aust. New Zeal. J. Med. 7: 309-311, 1977. [PubMed: 269694] [Full Text: https://doi.org/10.1111/j.1445-5994.1977.tb03695.x]
Scappaticci, S., Cerimele, D., Fraccaro, M. Clonal structural chromosomal rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner's syndrome. Hum. Genet. 62: 16-24, 1982. [PubMed: 7152523] [Full Text: https://doi.org/10.1007/BF00295599]
Scappaticci, S., Forabosco, A., Borroni, G., Orecchia, G., Fraccaro, M. Clonal structural chromosomal rearrangements in lymphocytes of four patients with Werner's syndrome. Ann. Genet. 33: 5-8, 1990. [PubMed: 2369072]
Schellenberg, G. D., Martin, G. M., Wijsman, E. M., Nakura, J., Miki, T., Ogihara, T. Homozygosity mapping and Werner's syndrome. (Letter) Lancet 339: 1002, 1992. [PubMed: 1348795] [Full Text: https://doi.org/10.1016/0140-6736(92)91590-5]
Schonberg, S., Niermeijer, M. F., Bootsma, D., Henderson, E., German, J. Werner's syndrome: proliferation in vitro of clones of cells bearing chromosome translocations. Am. J. Hum. Genet. 36: 387-397, 1984. [PubMed: 6324581]
Thomas, W., Rubenstein, M., Goto, M., Drayna, D. A genetic analysis of the Werner syndrome region on human chromosome 8p. Genomics 16: 685-690, 1993. [PubMed: 8325642] [Full Text: https://doi.org/10.1006/geno.1993.1248]
Thweatt, R., Goldstein, S. Werner syndrome and biological ageing: a molecular genetic hypothesis. BioEssays 15: 421-426, 1993. [PubMed: 8357345] [Full Text: https://doi.org/10.1002/bies.950150609]
Tri, T. B., Combs, D. T. Congestive cardiomyopathy in Werner's syndrome. (Letter) Lancet 311: 1052-1053, 1978. Note: Originally Volume I. [PubMed: 76976] [Full Text: https://doi.org/10.1016/s0140-6736(78)90786-9]
Wyllie, F. S., Jones, C. J., Skinner, J. W., Haughton, M. F., Wallis, C., Wynford-Thomas, D., Faragher, R. G. A., Kipling, D. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. (Letter) Nature Genet. 24: 16-17, 2000. [PubMed: 10615119] [Full Text: https://doi.org/10.1038/71630]
Ye, L., Nakura, J., Mitsuda, N., Fujioka, Y., Kamino, K., Ohta, T., Jinno, Y., Niikawa, N., Miki, T., Ogihara, T. Genetic association between chromosome 8 microsatellite (MS8-134) and Werner syndrome (WRN): chromosome microdissection and homozygosity mapping. Genomics 28: 566-569, 1995. [PubMed: 7490095] [Full Text: https://doi.org/10.1006/geno.1995.1189]
Yu, C.-E., Oshima, J., Fu, Y.-H., Wijsman, E. M., Hisama, F., Alisch, R., Matthews, S., Nakura, J., Miki, T., Quais, S., Martin, G. M., Mulligan, J., Schellenberg, G. D. Positional cloning of the Werner's syndrome gene. Science 272: 258-262, 1996. [PubMed: 8602509] [Full Text: https://doi.org/10.1126/science.272.5259.258]
Yu, C.-E., Oshima, J., Goddard, K. A. B., Miki, T., Nakura, J., Ogihara, T., Poot, M., Hoehn, H., Fraccaro, M., Piussan, C., Martin, G. M., Schellenberg, G. D., Wijsman, E. M. Linkage disequilibrium and haplotype studies of chromosome 8p11.1-21.1 markers and Werner syndrome. Am. J. Hum. Genet. 55: 356-364, 1994. [PubMed: 8037212]
Yu, C.-E., Oshima, J., Wijsman, E. M., Nakura, J., Miki, T., Piussan, C., Matthews, S., Fu, Y.-H., Mulligan, J., Martin, G. M., Schellenberg, G. D., Werner's Syndrome Collaborative Group. Mutations in the consensus helicase domains of the Werner syndrome gene. Am. J. Hum. Genet. 60: 330-341, 1997. [PubMed: 9012406]