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.We do not yetknow the identity of the gene (or genes) which, when mutated, cancause such a complex and devastating disease.But that a single geneticerror can cause diseases of this type is suggested by another disorderon Martin's list: Werner's syndrome.Werner's SyndromeWerner's syndrome is named for Otto Werner, who firstdescribed this condition in his thesis for the M.D.degree in Germanyin 1904, the same year that Gilford described his first patient.Like theHutchinson-Gilford syndrome, this is clearly a progerial disorder, inwhich affected individuals experience some form of an acceleratedaging process.It is nearly as rare; only about 200 cases have beendescribed to date.But Werner's syndrome is without doubt distinctfrom HGPS.In his original report, Werner described four siblingswith essentially identical symptoms: growth retardation, general atro-phy of muscle and connective tissues, an aged appearance due to gray-ing hair and wrinkled skin, and crippling joint deformities.But unlikeHGPS, the onset of definitive symptoms in Werner's syndrome (WS)rarely begins before age twenty.Affected individuals seem perfectly84 HUMAN GENETIC DISEASES THAT MIMIC THE AGING PROCESSnormal as children, but they generally stop growing early in the ado-lescent years.Men are rarely more than five feet tall, with women sev-eral inches shorter.The average age of death in Werner's patients isforty-four years.The accumulation of additional patients since Werner's time hasallowed a clearer picture of the symptoms defining this disease.Hairgraying and loss is one of the earlier symptoms, beginning, like growthretardation, during the adolescent years.It is usually not as completeas in HGPS.Secondary sexual hair develops reasonably normally inmany cases, but may be lost as the syndrome progresses.During thisperiod as well, patients start to display prematurely aged skin, althoughnot as extensively as individuals with HGPS.The skin of the feet andhands is particularly affected, exhibiting the thin, dry, pigmented con-dition seen in HGPS, but also including the development of very thickcalluses that sometimes ulcerate and even bleed.Facial skin also seemsvery old in appearance, due to loss of subcutaneous fat and nutritivecell layers.On the other hand skin in the trunk region is only mini-mally affected.There is also a general wasting of muscle tissue in the extremities,accompanied by loss of bone mass, again with reasonable maintenanceof both of these parameters in the trunk.The overall appearance is thusof small, old-looking limbs appended to a robust, young-lookingtrunk.The joints are often thickened and calcified, making movementsdifficult and painful.One of the most distinctive features of WS is thedevelopment of cataracts.Normally seen only in persons over fifty,cataracts develop in nearly all WS patients over thirty, setting in asearly as ten years of age in a few individuals.The cataracts usually affectboth eyes simultaneously.Other eye problems associated with old ageare also common in these individuals.As in HGPS, WS patients develop cardiovascular problems that area common cause of death, although in those afflicted with WS thereis a more generalized problem with occluded blood vessels that canlead to gangrene and limb amputation.This could be due to the factthat WS patients live longer.This longer survival may also account forother differences between Werner's and HGPS patients, such as theoccurrence of maturity-onset (type II) diabetes and certain cancers inWS patients in the third and fourth decades of life; cancer is also acommon cause of death in WS.Although somewhat sexually under-85 A MEANS TO AN ENDdeveloped, individuals with this disease are in fact often fertile, and anumber have reproduced.As with HGPS patients, fibroblasts takenfrom persons afflicted with WS show greatly reduced growth in vitro,comparable to fibroblasts taken from very old persons.Studies with fibroblasts from WS patients have provided insightinto the types of changes that occur in these cells as they age, and thesechanges appear to parallel those seen during normal aging.Fibroblasts(which are scattered throughout the entire body, especially in skin) areone of a number of cell types that produce a protein called collagen.Collagen is well known as the soft precursor substance of bones, laiddown in embryos and newborns and later fortified by calcium intoclassical hard bone.But collagen plays a much wider role in the body,in the form of something called extracellular matrix, a semi-rigid,lattice-like structure to which cells adhere, and which gives tissues andorgans their shape.Without collagen and extracellular matrix, the bodywould likely collapse down into a mass of tissue hanging from a skele-tal frame.The collagen secreted by fibroblasts is used to make up thisextracellular matrix.But fibroblasts are also capable of producing theenzyme collagenase, which degrades collagen.As fibroblasts senesce,either in vitro or in vivo, they switch from a collagen-producing to acollagenase-secreting (collagen-degrading) cell phenotype.Destruc-tion of the extracellular matrix by fibroblasts could certainly causemany of the features associated with aging, such as wrinkled and sag-ging skin, and possibly some of the apparent wasting in muscle tissue.A significant number of WS patients are born to consanguinous par-ents, particularly in Japan where first- and second-cousin marriages aremore common than in the West; about three-quarters of all WS caseshave been reported from Japan.The fact that WS occurs more fre-quendy in consanguinous marriages, and affects offspring of both sexes,indicates that it is an autosomal recessive defect.About one in 5000persons is estimated to carry the WS gene, leading to the appearanceof WS in about one in 25 million births.Determining exactly which au-tosomal gene is defective in WS has been somewhat easier to approachthan was the case for HGPS.Patients live longer, and occasionally evenhave offspring to whom the gene is passed.There is also a reasonablenumber of cases where more than one child is afflicted in the same fam-ily, which further supports the case for autosomal recessiveness andgreatly helps in tracing the chromosomal location of genes.86 HUMAN GENETIC DISEASES THAT MIMIC THE AGING PROCESSA close study of the inheritance pattern of WS in Japan and in theUnited States traced the underlying gene to the short arm of chromo-some 8.Using advanced techniques for gene mapping at the DNAlevel,* the chromosomal location of the WS gene was determined withsufficient accuracy to allow the very first isolation and sequencing ofan apparent aging-associated gene, described in a joint Japanese-U.S.report published in April 1996
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