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What do we know about the cause of Werner syndrome and progeria, the disease that leads to premature aging in children?

George M. Martin, professor of pathology and director of the Alzheimer's Disease Research Center at the University of Washington, comments:

"I appreciate this opportunity to communicate to your readers, as journalists have often overstated the significance of the genes for Werner syndrome and Hutchinson-Gilford progeria as keys to the understanding of aging. These are actually two distinctly different disorders; a major clinical difference is that the onset of the Hutchinson-Gilford syndrome (sometimes called progeria of childhood) occurs within the first decade of life, whereas the first evidence of Werner syndrome (sometimes called progeria of the adult) appears in adolescence, when the individual fails to undergo the usual growth spurt. A good clinician can make the diagnosis of Hutchinson-Gilford in the first two or three years of life.

"It is an exaggeration to refer to these genetic disorders as 'diseases of premature aging.' While patients do indeed have an external appearance of premature aging and suffer from some of the common ailments of older people, there are a number of clinical features that differ from that which is observed in most individuals as they age. For example, Werner syndrome patients develop neoplasms prematurely, but the neoplasms tend to be those derived from mesenchymal rather than epithelial cells; the latter are the main source of tumors of older people. Werner patients suffer from osteoporosis, but the distribution is unusual in that it is very severe in the long bones of the legs. They also develop unusual deposits of calcium in the soft tissues and ulcers around their elbows and ankles. Patients who have Hutchinson-Gilford syndrome experience arthritis of the hips, but it is a result of having been born with dislocated hips. Their clavicles also develop abnormally.

"Nevertheless, both these diseases are important to study because identifying the underlying mutations that cause them could enlarge our understanding of such important disorders as diabetes, cancer, cataracts and atherosclerosis. The autosomal recessive mutation responsible for Werner syndrome has recently been identified by a group led by Chang-En Yu of the University of Washington (see the April 12, 1996, issue of Science, Vol. 272, page 258). This mutation affects a member of a large family of enzymes, called helicases, that act 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 progeria is not yet known.

"The fact that a helicase mutation is responsible for the disorder lends support to several lines of evidence indicating that the somatic cells of Werner syndrome patients are especially prone to mutations. In this respect, they are similar to individuals who have Bloom syndrome, a recessive genetic disorder also caused by a defective helicase (Nathan A. Ellis et al. in Cell, Vol. 83, No. 4, page 655; November 17, 1995). The mutation underlying the Hutchinson-Gilford syndrome is probably a sporadic, autosomal-dominant one (W. T. Brown in American Journal of Clinical Nutrition, Vol. 55, No. 6(Supplement), page 1222S; June 1992). The responsible gene has not yet been identified, however, so we remain ignorant of its pathogenesis."

David Gems, a professor in the division of biological sciences at the University of Missouri at Columbia, offers a somewhat different view of progeria:

"Werner syndrome is the most common form of progeria. The first signs of this disorder appear only after puberty, with the full symptoms becoming manifest in individuals 20 to 30 years old. A much rarer progeria, Hutchinson-Gilford syndrome, develops earlier: victims die, apparently of old age, typically at around age 12. It is fortunate that this hereditary disease occurs very infrequently.

"The potential value of understanding the cause of diseases such as Werner syndrome is hard to overstate. Nowadays those involved in aging research increasingly 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. Viewed in this new light, the condition of aged friends and relatives, and of older people seen in the street, suddenly seems terrible to conceive: they are afflicted with a ghastly wasting disease, a plague whose effects are inescapably scripted by our own genes.

"Werner syndrome results from mutation of a single gene. Is it possible that by understanding the healthy version of the gene we can begin to learn how genes control lifespan and so take the first step down the road toward curing the disease of aging? Unfortunately, the answer is not yet at all certain, for two major reasons. First, it remains unclear whether the symptoms of Werner syndrome really correspond to an acceleration of the aging process or whether the resemblance to aging is merely superficial. Although Werner syndrome victims prematurely show some of the signs of aging (such as graying of the hair and hair loss, atherosclerosis, osteoporosis and type II diabetes mellitus), they fail to show others. For example, they exhibit no premature cognitive decline or Alzheimer's symptoms. And they experience many 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).

"The second problem is the lack of an animal model for Werner syndrome that could be employed to study the disease in detail. Progeria is dreadful enough for those suffering from it without having gerontologists hovering around wanting to do tests and snip off bits of you.

"In April 1996 the study of Werner syndrome was greatly advanced by the announcement of the cloning and sequencing of WRN, the gene which when mutated gives rise to the disease. In some instances, the identity of a gene provides immediate insight into the nature of the disease resulting from defects in it. This was true, for example, when the gene for cystic fibrosis was cloned. Unfortunately, as is more often the case, the WRN gene is more enigmatic. It encodes a protein that most closely resembles a DNA helicase. DNA helicases are enzymes involved in DNA repair and recombination, suggesting that Werner syndrome results from failure in these processes.

"There are reasons to treat this hypothesis cautiously, however. The capacity of the WRN protein to act as a helicase has yet to be demonstrated, and there are other genetic diseases resulting from mutations in genes encoding DNA helicases that do not resemble Werner syndrome. Xeroderma pigmentosum and Cockayne 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 putative DNA helicase are the cause of Werner syndrome, but it is not known how this defect results in the disease.

"It is possible that the most valuable short-term consequence of knowing the identity of the Werner syndrome gene is 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 whose genetic equivalent of the WRN gene contains the same mutation that causes Werner syndrome in humans and, if so, whether the mutation produces accelerated aging in the mouse. The latter question is particularly difficult because aging is still so poorly understood. The primary determinants of aging in animals are unknown. It is not even clear whether aging is determined by organism-wide processes, such as immunologic or hormonal changes, or by events occurring independently in different cells, tissues or organs. Arguably, only with the experimental flexibility provided by an animal model will it be possible to establish whether accelerated aging actually occurs in Werner syndrome and, if so, how this aging occurs."

Gerard Schellenberg of the University of Washington, who participated in the recent cloning of the WRN gene, adds some additional information:

"Werner syndrome is an inherited disease that is extremely rare, affecting somewhere between one in 100,000 and one in 1,000,000 individuals. The inheritance is autosomal recessive, meaning that someone will develop Werner syndrome only if both copies of the disease gene are mutated.

"The gene responsible for the syndrome was localized to chromosome 8 in 1992 by Dennis Dryna and his colleagues. In 1996 my group in Seattle, along with a number of collaborators, cloned the gene responsible for the disease. The responsible gene encodes a previously unknown protein that has a strong homology to a class of enzymes called helicases. These enzymes unwind DNA or RNA; in other words, they convert a double-stranded molecule into two single-stranded molecules. Higher organisms, including humans, have a number of different helicase genes. Each probably functions in a different process requiring the unwinding of DNA or RNA. Examples of processes in which helicases are required are DNA replication, repair and transcription, to name just a few.

"The function of 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. We do know 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. Having the gene in hand gives a tool for beginning to answer these questions."

And finally, Ray Thweatt in the department of biology at West Virginia University suggests some useful references for more information on progeria and on theories of aging:

How and Why We Age by Leonard Hayflick. Ballantine Books, 1994.

"Progeria: Medical Aspects, Psychosocial Perspectives and Intervention Guidelines" by Hanoch Livneh, Richard E Antonak and Sheldon Maron, in Death Studies Vol. 19, page 433; 1995.

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