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Nowadays those involved in aging research view aging in terms of a genetic disease rather than as a natural, evolution-driven process by which the old make way for the young. A condition of aged friends and relatives seems terrible to conceive; they are afflicted with a ghastly wasting disease, a plague whose effects are inescapable because of our own genes. People plagued with Werner syndrome do not even have the opportunity to experience this natural progression we call aging, instead this disease causes its victims to die of old age by their mid 40’s or 50’s.
Just about everyone dreads the physical decline often associated with aging, but people with the rare inherited disease known as Werner syndrome have to face the aging process far sooner than most. Unexpectedly, while they are still in their early twenties, their hair grays, their skin loses its suppleness, and their vision clouds from cataracts. Even worse, they get cancer, heart disease, and a host of other diseases that usually don’t strike until later in life. Most people afflicted with Werner syndrome die before age 50. Aging experts have long wondered just what kind of molecular defect could cause such a striking acceleration of the aging process.
Werner Syndrome is a rare progressive disorder that is characterized by the appearance of unusually accelerated aging. Although the disorder is typically recognized by the third or fourth decades of life, certain characteristic findings are present beginning during childhood, adolescence, and early adulthood (as seen in the picture below).
Werner Syndrome may also be characterized by development of a distinctive high pitched voice; eye abnormalities, including premature clouding of the lenses of the eyes due to aging; and certain endocrine defects, such as impaired functioning of the ovaries in females or testes in males or abnormal production of the hormone insulin by the pancreas and resistance to the effects of insulin. In addition, individuals with Werner Syndrome develop progressive thickening and loss of elasticity of artery walls. Some affected individuals may also be susceptible to developing certain tumors. Progressive arteriosclerosis, malignancies, and associated abnormalities may result in potentially life-threatening complications by approximately the fourth or firth decade of life due to Werner syndrome.
Just recently, an international team of geneticists, led by Gerard Schellenberg of the Veterans Affairs Puget Sound Health Care System in Seattle, discovered the gene at fault in Werner syndrome. Aging experts are already delighted by this magnificent finding. This is important because it is the first time that any gene that has been associated with aging has been identified. One reason for the excitement is that the structure of the protein encoded by the gene indicates that it is a helicase, an enzyme that acts to unwind DNA and sometimes RNA in order to facilitate such processes as the replication, repair, transcription, and recombination of DNA. Some helicases may also be important in ensuring the accuracy of chromosomal segregation. Precisely which subset of these functions is critical in producing the pathology of Werner syndrome is not yet known. This suggests that the mutations that cause Werner Syndrome may exert their harmful effects by upsetting one or another of those activities. The fact that these helicase mutations are responsible for the disorder, leads support to several lines of evidence that indicate that the somatic cells of Werner Syndrome patients are especially prone to mutations. By testing out what does happen, researchers hope they will eventually be able to design a treatment that slows the aging process and cures Werner syndrome.
The gene may also yield insights into cancer, because Werner syndrome patients suffer from many forms of cancer or rare tumors. From this, it can be concluded that the Werner syndrome gene is not only an aging gene, but also a cancer gene.
Schellenberg says he began looking for the Werner syndrome gene in 1992. At that point, Makoto Goto from Tokyo Metropolitan Otsuka Hospital and his colleagues had already shown that the gene is located on the short arm of chromosome 8 by genetic linkage studies-comparing the inheritance of the disease with that of markers at known locations on the chromosomes. To continue the hunt, scientists began by doing further genetic studies aimed at narrowing down the gene’s location. He then wanted to sequence DNA from the suspect region and scan the sequence to find likely genes. “My philosophy was to bring all the different gene identification technologies to bear [on this problem],” he recalls.
Other groups were also searching for the gene and a remarkable spirit of cooperation between competing groups aided the hunt. A team of American scientists and that of rival gene-hunter Tetsuro Miki of Osaka University Medical School shared tissue samples from affected families in order to improve each other’s chances of pinning down the gene’s location. Schellenberg credits the additional families and subjects with helping his team to narrow the search to a section of chromosome encompassing just a million bases-still a lot of DNA, but manageable for the detailed sequencing effort that followed.
This began in early 1995, when Chang-En Yu and Junko Oshima from Schellenberg’s lab in Seattle teamed up with sequencing expert Ying-Hui Fu from Darwin Molecular Corp., also in Seattle. Each time the researchers came across a gene in the DNA they were sequencing, they looked to see whether people with Werner syndrome, had mutations there. Finally, after sequencing 650,000 bases-possibly the most DNA ever sequenced in a gene hunt-and identifying four known genes and six new ones, whose sequences did not appear in the databases, the scientists found the one they were looking for.
To date, Schellenberg’s group has found four different mutations disrupting this gene in Werner syndrome patients. Four mutations in Werner syndrome patients were detected in the gene corresponding to chromosome eight. Two mutations were nonsense mutations creating premature stop codons. Four Japanese Werner syndrome patients, the offspring of first cousin marriages, and one Caucasian, from a second cousin marriage were homozygous for the mutation. The second mutation was found in one Japanese patient who is the offspring of a first cousin marriage and homozygous for the mutation. These mutations were not observed in 48 Caucasian or 96 Japanese control individuals. The third mutation, identified in a Syrian family, is a splice-junction mutation. This would result in the exclusion of the exons from the final mRNA. The exon is the DNA segment or segments of the gene that are transcribed and translated by the donor cell. The fourth mutation identified was similar to this exhibiting a missing exon and flanking genomic segments which results in a frame shift of codons. This Werner syndrome patient is the offspring of a first cousin marriage and is homozygous for this mutation.
As you can see from this evidence, the mode of inheritance appears to be from inbred marriages. Werner syndrome is a recessive disease, meaning symptoms will not occur unless both copies of the gene are mutated and present.
A case study was conducted on twenty-one Japanese families. Of those, thirteen had marriages between the first cousins and two other families were suspected of the same. Eleven of the families consisted of a single generation, nine had two generations, and one had three generations. From these twenty-one families, seven of them had several offspring affected by Werner syndrome. In addition, from the sixty-three individuals that were studied, thirty-one of them were affected by the syndrome. One of the 144 healthy people who served as controls also had one of these mutations, but in only one of the two copies of the gene. (Because Werner syndrome is a disease, symptoms do not develop unless both gene copies are mutated.) “We had started wondering where it was, but then it showed up and it was absolutely clear,” says molecular biologist David Galas of Darwin Corp. “I think it’s the first human gene that’s been identified by large-scale sequencing like this, but I think this [approach] is going to become more and more commonplace.” Meanwhile, Miki had also been closing in on the gene, but was still not there when Schellenberg let him know the search was over.
The sequence of the Werner syndrome gene, which encodes a protein containing 1432 amino acids, does not exactly match anything else in the databases. But because part of it closely resembles the sequences of genes that code for known helicases, Schellenberg and his colleagues assume this gene, too, codes for one, although they have not proven that directly.
Assuming that it does, however, that “tells you straight away that there are DNA transactions that are important [for Werner syndrome],” says S. Michael Jazwinski, a molecular geneticist at Louisiana State University Medical Center in New Orleans. Exactly what kind of transaction it still remains unclear.
There exist a half-dozen or so known helicases that unwind the DNA, and prepare the way for DNA replication or repair, gene expression, chromosome recombination, as well as the shuffling of chromosomal segments that takes place during formation of the germ cells. Derangement in any of these processes has the potential to damage the genetic material, and thus the cell. This in turn could cause cells to function poorly, causing premature aging associated with Werner syndrome.
If the DNA damage happened to inactivate tumor suppressor genes or active oncogenes, it might also cause cells to grow out of control and produce cancerous tumors. In fact, there is already evidence that a faulty helicase can cause cancers. Recently a team led by geneticist James German of the New York Blood Center in New York City pinpointed the gene for Bloom’s syndrome, another rare disease associated with several cancers and numerous chromosome abnormalities, and it, too, specifies a helicase.
Still unclear, however, is why a helicase mutation would cause the unusual cancers seen in Werner syndrome patients. Most cancers arise in epithelial tissue-the skin or the linings of the colon and lungs and of the mammary ducts. But in the April issue of Cancer Epidemiology, Biomarkers and Prevention, Japanese and U.S. researchers, including Miller, report that the cancers associated with Werner syndrome are just as likely to develop in nonepithelial tissue, such as muscles and connective tissue.
But before researchers can explore this issue or pursue analogies between the Werner syndrome gene and known helicase genes, they will need to test the hypothesis that it really does code for a helicase. The reason for this caution is that the capacity of the WRN protein to act as a helicase has yet to be demonstrated and there are several other genetic diseases resulting from mutations in genes encoding DNA helicases that do not resemble Werner syndrome. Xeroderma and Cochayne syndrome, which also result from defective DNA helicases, result in increased sensitivity of cells to ultraviolet radiation. This is thought to happen because ultraviolet rays damage DNA, which cannot be properly repaired by the mutant helicases. Yet, Werner syndrome cells are not abnormally sensitive to ultraviolet radiation. In short, it is known that defects in a presumed DNA helicase are the cause of Werner syndrome, but is not know how this defect results in the disease. The next step is to explore what effects, if any, mutations in the WRN gene have on DNA repair or other aspects of DNA metabolism.
Still, as Schellenberg cautions, answering these questions will not explain everything about aging. “I don’t want to sell Werner syndrome as a total mimic of aging,” he emphasizes. He also notes that there are some essential differences between how people with Werner syndrome age and the way everyone else ages and not just in the kinds of cancer, they suffer from. Although prematurely old, the patients do not develop Alzheimer’s disease or high blood pressure, diseases, which are typically associated with old age. Instead, they experience symptoms not associated with normal aging such as ulceration of the skin, particularly around the ankles, alteration of the vocal chords resulting in a high-pitched voice, and an absence of the growth spurt that normally occurs after puberty.
Even if the gene does play a role in normal aging, it cannot be acting alone. Researchers estimate that some 70% of human genes are involved in some way in determining how long people live.
It is possible that the most valuable piece of information gained is knowing the identity of the Werner syndrome gene and that it may allow the development of an animal model for studying the disease. Researchers have not yet determined whether it is possible to create a mouse, which as the genetic equivalent of the WRN gene and that contains the same mutation that causes Werner syndrome in humans. Researchers are also unsure whether the mutation would produce accelerated aging in the mouse because aging is such a difficult process to understand, and that the primary determinants of aging in animals remain unknown. In addition, using yeast as a model for human aging in general may give insight into the mechanisms of Werner syndrome and related diseases. A yeast protein similar to the human WRN protein, called SGS1, has been found. Mutations in SGS1 cause yeast to have a shorter lifespan than yeast cells without the mutation, and shown other signs typical of aging in yeast, such as an enlarged and fragmented nucleolus. It is not even understood whether aging is determined by organism-wide processes, such as hormonal changes, or by events occurring individually in different cells, tissues, or organs. Only with the experimental flexibility provided by an animal model would it be possible to establish whether accelerated aging actually occurs in Werner syndrome and how this aging occurs.
The function of the Werner syndrome helicase is currently unknown. What is clear is that subjects with the syndrome probably do not produce a functional form of this protein. It is known that DNA in affected subjects appears to contain a large number of damaged sites. This accumulation of DNA damage is probably the cause of the symptoms we call Werner syndrome. Cells from Werner syndrome subjects do not appear to be defective for any known DNA repair process, so the primary defect probably involves a defect in a process that causes DNA damage, rather than one that repairs damage caused by other agents. Whatever the specific mechanisms involved in the Werner syndrome phenotype, identification of the Werner syndrome gene now provides evidence that at least some components of normal aging and disease susceptibility in late life may be related to disfunctions in DNA metabolism. Fortunately, we have the responsible gene in hand, giving a tool to begin answering all of these puzzling questions.
The Aging Gene Discovered: Werner Syndrome
Adoue, Daniel. Werner’s Syndrome. New England Journal of Medicine vol 337. 1997.
This is a shocking picture of someone diagnosed with Werner’s syndrome. It is a good picture to understand exactly what this syndrome does to a persons body. This 38 year old man looks as if he is much older.
Bauer, Eugene A. “Diminished Response of Werner’s Syndrome Fibroblasts to Growth Factors PDGF and FGF”. Science, vol 234: 1240-1244, 1996.
Patient’s with Werner’s syndrome, undergo an accelerated aging process that leads to premature death. Fivroblasts from such patients typically grow poorly in culture. Here it is shown that fibroblasts from a patient with Werner’s syndrome have a markedly attenuated mitogenic response to platelet-derived growth factor and fibroblast growth factor.
Goto, Makoto.; Rubenstein, Mark. “Genetic linkage of Werner’s syndrome to five markers on chromosome 8″. Nature v. 355. 1992.
This is an article about progeria and it’s linkage to familial diseases. It is also about the linkage found of werner’s syndrome to certain markers on a chromosomes.
Khraishi, M.; Howard, B. A patient with Werner’s syndrome and osteosarcoma presenting as scleroderma. J. Rheum. 19: 810-813, 1992.
This is an article about a specific case of a person with both Werner’s syndrome and osteosarcoma. It describes the case and gives some examples of the early onset problems that they had.
Martin, George. ” What do we know about the cause of Werner Syndrome and progeria, the disease that leads to premature aging in children”. Scientific American. University of Washington, 1992.
This article asks many scientists questions about Werner’s syndrome. In addition, it contrasts Werner’s syndrome and Hutchinson-Gilford syndrome giving many different scientific opinions on both syndromes.
Morozov, Vladimir; Mushegian, Arcady. “A putative nucleic acid-binding domain in Bloom’s and Werner’s syndrome helicases”. Trends in Biochemical Sciences v. 22. United Kingdom, 1997.
The identification of a putative necleic acid-binding domain in Bloom’s and Werner’s syndrome helicases is reported. These disorders are associated with a notable predisposition to various cancers, and the proteins involved are both very similar to helicases of the RecQ family.
Moser, Michael. “WRN mutations in Werner Syndrome”. University of Washington, Seattle: 1998.
Werner syndrome is one of a group of human genetic diseases that have recently been linked to deficits in cellular helicase function. This is a review of the spectrum of WS-associated WRN mutations, the organization and potential functions of the WRN protein, and potential mechanistic links between the loss of the WRN function and pathogenesis of the WS clinical and cellular phenotypes.
Salk, Darrell. Werner’s Syndrome and Human Aging. Plenum Press, New York, 1985.
This is about a United States-Japan cooperative seminar on Werner’s syndrome and human aging. It explains what Werner’s syndrome is and gives many useful facts about Werner’s syndrome.
Schellenberg, Gerard. “Premature Aging Gene Discovered”. Scientist. New Orleans, June 1998.
The gene that causes Werner’s Syndrome, which causes a rapid acceleration in aging, appears to encode a DNA-unwinding enzyme, and may provide clues to cancer and other diseases of old age.
Yu, Chang-En; Oshima, Junko. “Positional Cloning of the Werner’s syndrome Gene”. Science, vol 272. Geriatric Research Education and Clinical Center. Seattle, 1996.
The identification of a mutative putative helicase as the gene product of the Werner’s syndrome gene suggests that defective DNA metabolism is involved in the complex process of aging in Werner’ syndrome patients.
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