Werner syndrome (WS) or Werner's syndrome, also known as "adult
progeria",
[James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. .] is a rare
autosomal recessive disorder which is characterized by the appearance of premature
aging
Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
.
Werner syndrome is named after the German scientist
Otto Werner. He identified the syndrome in four siblings observed with premature aging, which he explored as the subject of his dissertation of 1904.
It has a global incidence rate of less than 1 in 100,000 live births
(although incidence in Japan and Sardinia is higher, affecting 1 in 20,000–40,000 and 1 in 50,000, respectively).
1,300 cases had been reported as of 2006.
Affected individuals typically grow and develop normally until puberty; the mean age of diagnosis is twenty-four, often realized when the
adolescent
Adolescence () is a transitional stage of human physical and psychological development that generally occurs during the period from puberty to adulthood (typically corresponding to the age of majority). Adolescence is usually associated w ...
growth spurt
Human height or stature is the distance from the bottom of the feet to the top of the head in a human body, standing erect. It is measured using a stadiometer, in centimetres when using the metric system or SI system, or feet and inches when u ...
is not observed.
The youngest person diagnosed was six years old.
The median and mean ages of death are 47–48 and 54 years, respectively.
[Oshima J, Martin GM, Hisama FM. Werner Syndrome. 2002 Dec 2 pdated 2012 Dec 13 In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews nternet Seattle (WA): University of Washington, Seattle; 1993-. Available from:https://www.ncbi.nlm.nih.gov/books/NBK1514/] The main causes of death are
cardiovascular disease
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
and cancer.
Presentation
Werner syndrome patients exhibit growth retardation, short stature, premature graying of hair,
alopecia
Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...
(hair loss),
wrinkling, prematurely aged faces with
beaked noses, skin
atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
(wasting away) with
scleroderma
Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...
-like
lesion
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals.
Types
There is no de ...
s,
lipodystrophy
Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissu ...
(loss of fat tissues), abnormal fat deposition leading to thin legs and arms, and severe
ulcer
An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughin ...
ations around the
Achilles tendon
The Achilles tendon or heel cord, also known as the calcaneal tendon, is a tendon at the back of the lower leg, and is the thickest in the human body. It serves to attach the plantaris, gastrocnemius (calf) and soleus muscles to the calcane ...
and
malleoli (around ankles). Other symptoms include change in voice (weak, hoarse, high-pitched), atrophy of
gonad
A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...
s leading to reduced
fertility
Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...
,
bilateral cataracts (clouding of lens), premature
arteriosclerosis
Arteriosclerosis, literally meaning "hardening of the arteries", is an umbrella term for a vascular disorder characterized by abnormal thickening, hardening, and loss of elasticity of the walls of arteries; this process gradually restricts th ...
(thickening and loss of elasticity of arteries),
calcinosis (calcium deposits in blood vessels),
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
(blockage of blood vessels),
type 2 diabetes
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
,
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk.
It is the most common reason f ...
(loss of bone mass),
telangiectasia
Telangiectasias (), also known as spider veins, are small dilated blood vessels that can occur near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. These dilated blood vessels can develop anywhere ...
, and
malignancies
Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer.
A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...
.
The prevalence of rare cancers are increased in individuals with Werner syndrome.
Gene expression
Gene
transcription changes found in WS cells are strikingly similar to those observed in normal aging.
At the level of gene expression, WRN protein deficiency causes changes in the pattern of
gene expression
Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...
that markedly resemble those of normal old age.
Clinical symptoms
The mutation in the ''
WRN'' gene that causes Werner syndrome is autosomal and recessive, meaning that affected people must inherit a copy of the gene from each parent. Patients display rapid premature aging beginning in young adulthood, usually in their early twenties.
Diagnosis is based on six cardinal symptoms: premature graying of the hair or hair loss, presence of bilateral cataracts, atrophied or tight skin, soft tissue calcification, sharp facial features, and an abnormal, high-pitched voice.
Patients are generally short-statured due to absence of the adolescent growth spurt. Patients also display decreased fertility.
The most common symptom of the six is premature graying and loss of hair. This is also generally the earliest observed symptom, with hair loss occurring first on the scalp and the eyebrows.
Werner syndrome patients often have skin that appears shiny and tight, and may also be thin or hardened.
This is due to atrophy of the subcutaneous tissue and dermal fibrosis.
Over time, the characteristic facial features may be more apparent due to these skin conditions. Other associated skin conditions include ulcers,
which are very difficult to treat in Werner syndrome patients, and are caused in part by decreased potential of skin cells for replication.
WS
cataract
A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...
s are distinctly different from those of normal aging. They are associated with problems in the
lens
A lens is a transmissive optical device that focuses or disperses a light beam by means of refraction. A simple lens consists of a single piece of transparent material, while a compound lens consists of several simple lenses (''elements'') ...
posterior cortex Posterior cortex usually means the posterior (back) part of the complete cerebral cortex and includes the occipital, parietal, and temporal cortices. In other words, the posterior cortex includes all the cerebral cortex without the frontal corte ...
and subcapsular regions. These cataracts are generally treatable with
cataract surgery
Cataract surgery, also called lens replacement surgery, is the removal of the natural lens (anatomy), lens of the human eye, eye that has developed a cataract, an opaque or cloudy area. The eye's natural lens is usually replaced with an artific ...
, which should restore normal vision.
Symptoms become apparent in the late teens and early twenties and continue to progress. Most patients live to about fifty years of age. The most common causes of death for people are associated diseases and complications, especially atherosclerosis and cancer.
Associated diseases
Werner syndrome patients are at increased risk for several other diseases, many associated with aging.
Atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
, the thickening of artery walls due to cholesterol buildup, is one common complication.
While normal atherosclerosis generally involves the major arteries, smaller arterioles are more likely to be affected.
It is possible nervous system disorders are associated. Brain atrophy is present in 40% of patients.
Osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk.
It is the most common reason f ...
, the loss of bone mineral density common in post-menopausal women, is another common symptom. In contrast with the normal population, the rate of osteoporosis is especially high for male patients.
Diabetes mellitus
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
is another common accompaniment.
Skin ulcers occur in about 75% of patients – and can be difficult to treat. If skin ulcers become badly infected or develop
gangrene
Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...
, they often require
amputation
Amputation is the removal of a Limb (anatomy), limb or other body part by Physical trauma, trauma, medical illness, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as cancer, malign ...
. Unlike most other related diseases and complications, these ulcers are not associated with normal aging.
Patients are also at an increased risk of cancer, especially
malignant melanoma.
Soft-tissue sarcomas are the most common cancer types.
Other types of skin cancer, other epithelial cancers such as
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by ...
and
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
cancers, MDS (
myelodysplastic syndrome
A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
), and MFH (
malignant fibrous histiocytoma
Undifferentiated pleomorphic sarcoma (UPS), also termed pleomorphic myofibrosarcoma, high-grade myofibroblastic sarcoma, and high-grade myofibrosarcoma, is characterized by the World Health Organization (WHO) as a rare, poorly differentiated neopl ...
) are also prevalent among.
Mutations in the ''WRN'' gene, especially
single-nucleotide polymorphisms
In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
(SNPs), are associated with many of the cancers and other associated diseases. ''WRN'' SNPs correlate with cancers such as sarcomas and non-Hodgkin lymphomas, as well as diabetes and cardiovascular problems including atherosclerosis.
Causes
Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the gene, ''
WRN'', the only gene currently attributed to cause Werner syndrome.
''WRN'', which lies on
chromosome 8 in humans, encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the
RecQ helicases. RecQ helicases are a special type of helicase that function at unique times during DNA repair of doubled stranded breaks, which are a form of
DNA damage that results in a break of both strands of DNA. Thus, RecQ helicases are important for maintaining DNA stability, and loss of function of these helicases has important implications in the development of Werner syndrome. In addition to the central domain, there are three exonuclease domains at the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
and a Helicase and Ribonuclease D C-terminal (HRDC) domain at the
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein
Proteins are large biomolecules and macromolecules that comp ...
.
When functioning normally, the ''WRN'' gene and its associated protein (WRNp) are important for maintaining genome stability.
WRNp is active in unwinding DNA, a step necessary in DNA repair and
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
.
Specifically, it has an important role in responding to replication malfunctions, particularly
double-stranded breaks, and stalled replication machinery.
WRNp may reactivate replication by preventing unwanted recombination processes from occurring or by promoting recombination, depending on the type of DNA damage. In addition, WRNp physically interacts with or binds to several other proteins that are involved in processing DNA.
For example, when WRNp binds to RPA, its helicase activity is stimulated. WRNp also physically interacts with
p53, a tumor suppressor gene that stops the formation of tumors and the progression of cancers, which inhibits the exonuclease activity of the WRNp.
Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.
DNA repair processes
The finding that WRN protein interacts with
DNA-PKcs and the
Ku protein complex, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of
non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...
(NHEJ).
WRN protein also physically interacts with the major NHEJ factor X4L4 (
XRCC4
DNA repair protein XRCC4 (hXRCC4) also known as X-ray repair cross-complementing protein 4 is a protein that in humans is encoded by the ''XRCC4'' gene. ''XRCC4'' is also expressed in many other animals, fungi and plants. hXRCC4 is one of severa ...
-
DNA ligase 4 complex).
X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.
WRN protein appears to play a role in resolving recombination intermediate structures during
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
al repair (HRR) of DNA double-strand breaks.
WRN protein participates in a complex with
RAD51
DNA repair protein RAD51 homolog 1 is a protein encoded by the gene ''RAD51''. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to t ...
, RAD54,
RAD54B and
ATR proteins in carrying out the recombination step during inter-strand
DNA cross-link repair.
Evidence was presented that WRN protein plays a direct role in the repair of
methylation
Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
induced
DNA damage. This process likely involves the
helicase
Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
and
exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is th ...
activities of WRN protein that operate together with
DNA polymerase beta in long patch
base excision repair
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
.
Effects on cell structure and function
Mutations which cause Werner syndrome all occur at the regions of the gene which encode for protein, and not at non-coding regions.
There are 35 different known mutations of ''WRN'', which correspond to
stop codons,
insertions, or
deletions that result in a
frameshift mutation.
These mutations can have a range of effects. They may decrease the stability of the
transcribed messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
(mRNA), which increases the rate at which they are degraded. With less mRNA, less is available to be
translated into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein, leading to the loss of its
nuclear localization signal sequence, thus it is no longer transported into the nucleus where it interacts with the DNA. This leads to a reduction in DNA repair.
Furthermore, mutated proteins are more likely to be degraded than normal WRNp.
Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increasing the survival of these dysfunctional cells. Cells of affected individuals also have reduced lifespan in
culture
Culture ( ) is a concept that encompasses the social behavior, institutions, and Social norm, norms found in human societies, as well as the knowledge, beliefs, arts, laws, Social norm, customs, capabilities, Attitude (psychology), attitudes ...
, have more chromosome breaks and
translocations and have extensive deletions.
Patients with Werner syndrome lose the RecQ helicase activity in the WRN protein because of the loss of its C-terminus region, but the mechanism by which this happens is unclear. The loss of the helicase activity can have far-reaching consequences in terms of cell stability and mutation. One instance of these consequences involves
telomeres (the ends of chromosomes). It is thought that the WRN helicase activity is important not only for DNA repair and recombination, but also for maintaining telomere length and stability. Thus, WRN helicase is important for preventing catastrophic telomere loss during DNA replication.
In a normal cell, the telomeres undergo repeated shortening during the
cell cycle
The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
, which can prevent the cell from dividing and multiplying. This event can be counteracted by
telomerase
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
, an enzyme that extends the ends of the chromosomes by copying the telomeres and synthesizing an identical, but new end that can be added to the existing chromosome.
However, patients with Werner syndrome often exhibit accelerated telomere shortening, indicating that there may be a connection between the loss of the WRN helicase activity and telomere and cell instability. While evidence shows that telomere dysfunction is consistent with the premature aging in WS, it has yet to be determined if it is the actual cause of the genomic instability observed in cells and the high rate of cancer in WS patients.
Without the WRN protein, the interwoven pathways of DNA repair and telomere maintenance fail to suppress cancer and the aging symptoms seen in patients with Werner syndrome. Events such as rapid telomere shortening cause WS cells to exhibit low responses to overall cellular stress. In addition to telomere dysfunction, over-expression of
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. and
oxidation
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
can induce this type of response. High stress causes a synergistic effect, where WS cells become even more sensitive to agents that increase cell stress and agents that damage DNA. As a result, WS cells show a drastic reduction in replicative lifespan and enter into a stage of aging prematurely. The accumulation of these damaged cells due to telomere shortening over many years may be indicative of why WS symptoms only appear after an individual is about twenty years old.
Protection of DNA against oxidative damage
WRN protein was found to have a specific role in preventing or repairing DNA damages resulting from chronic
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
, particularly in slowly replicating cells.
This finding suggested that WRN may be important in dealing with oxidative DNA damage that underlies normal aging
(see
DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of DNA damage (naturally occurring), naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although ...
).
Diagnosis
Treatment
A cure for Werner syndrome has not yet been discovered. It is often treated by managing the associated diseases and relieving symptoms to improve quality of life. The skin ulcers that accompany WS can be treated in several ways, depending on the severity. Topical treatments can be used for minor ulcers, but are not effective in preventing new ulcers from occurring. In the most severe cases, surgery may be required to implant a
skin graft
Skin grafting, a type of graft (surgery), graft surgery, involves the organ transplant, transplantation of skin without a defined circulation. The transplanted biological tissue, tissue is called a skin graft.
Surgeons may use skin grafting to ...
or amputate a limb if necessary. Diseases commonly associated with WS such as diabetes and cancer are treated in generally the same ways as they would be for a non-Werner syndrome individual. A change in diet and exercise can help prevent and control arteriosclerosis, and regular cancer screenings can allow for early detection of cancer.
There is evidence that suggests that the
cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
-suppressive anti-inflammatory drug
SB203580 may be a possible therapeutic option for patients with WS. This drug targets the
p38 signaling pathway, which may become activated as a result of genomic instability and stalled replication forks that are characteristic mutations in WS. This activation of p38 may play a role in the onset of premature cell aging, skin aging, cataracts, and graying of the hair. The p38 pathway has also been implicated in the inflammatory response that causes atherosclerosis, diabetes, and osteoporosis, all of which are associated with WS. This drug has shown to revert the aged characteristics of young WS cells to those seen in normal, young cells and improve the lifespan of WS cells ''in vitro''. SB203580 is in the clinical trial stages, and the same results have not yet been seen ''in vivo''.
In 2010,
vitamin C
Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...
supplementation was found to reverse the premature aging and several tissue dysfunctions in a genetically modified mouse model of the disease. Vitamin C supplementation also appeared to normalize several age-related molecular markers such as the increased levels of the transcription factor
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
. In addition, it decreases activity of genes activated in human WS and increases gene activity involved in tissue repair. Supplementation of vitamin C is suspected to be beneficial in the treatment of human WS, although there was no evidence of anti-aging activity in nonmutant mice.
In general, treatments are available for only the symptoms or complications and not for the disease itself.
History
Otto Werner was the first to observe Werner syndrome in 1904 as a part of his dissertation research. As a German
ophthalmologist
Ophthalmology (, ) is the branch of medicine that deals with the diagnosis, treatment, and surgery of eye diseases and disorders.
An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a ...
, Werner described several progeria-like features and juvenile
cataract
A cataract is a cloudy area in the lens (anatomy), lens of the eye that leads to a visual impairment, decrease in vision of the eye. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colours, blurry or ...
s in many of his patients. He noticed these symptoms particularly in a family with four sequential children who all showed the characteristics of the syndrome at around the same age. He assumed the cause to be genetic, though most of his evidence was clinical. Between 1934 and 1941, two internists from New York, Oppenheimer and Kugel, coined the term "Werner Syndrome", igniting a wave of interest and research on the disease.
During that time, Agatson and Gartner suggested a possible link between WS and cancer. However, it was not until 1966 that there was a general consensus on the autosomal recessive mode of inheritance for the syndrome. By 1981,
geneticist
A geneticist is a biologist or physician who studies genetics, the science of genes, heredity, and variation of organisms. A geneticist can be employed as a scientist or a lecturer. Geneticists may perform general research on genetic process ...
s had located the ''
WRN'' gene on chromosome 8, leading to its cloning in 1996. This cloning of the WRN gene was significant because it revealed the predicted WRN protein was made from a family of DNA
helicase
Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
s.
Prior to 1996, WS was thought to be a model for accelerated aging. Since the discovery of the gene, it has become clear that the premature aging displayed in WS is not the same, on a cellular level, as normal aging. The role of WRN in DNA repair and its exonuclease and helicase activities have been the subject of many studies in recent years.
Since the initial discovery in 1904, several other cases of WS have been recorded. Many of these cases have occurred in Japan, where a
founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, us ...
has caused a higher incidence rate than in other populations. The incidence rate of WS in Japan is approximately 1 case per 100 thousand people (1:100,000), a large contrast with the rate of incidence for the rest of the world, which is between 1:1,000,000 and 1:10,000,000. A founder effect is also apparent in Sardinia, where there have been 18 recorded cases of WS.
Society and culture
In the
''Metal Gear'' franchise, several characters visually suffer from the effects of Werner Syndrome. The first character is
Solid Snake
, real name David, is a fictional character and one of the protagonists of Konami's ''Metal Gear'' series, created by Hideo Kojima. He is depicted as a former United States Army Special Forces, Green Beret and highly skilled special operations so ...
, who suffers from rapidly accelerated aging, despite being a young man. By the time of his early 40s, he appears to be in his early 70s. This is revealed to be the side effect of being a genetically engineered "test-tube baby", specifically made to be a clone of
Big Boss. Solid Snake's genetic code was deliberately modified to make him rapidly age and die prematurely, to ensure he could not turn rogue against a powerful
shadow government named "The Patriots". Big Boss' genetic material was also used to create two other clone children, named Liquid Snake, and Solidus Snake. Liquid Snake is the main antagonist of the 1998 entry in the franchise,
''Metal Gear Solid''. While not visually suffering from the effects of Werner's Syndrome, he is injected with a nanomachine-borne virus named "FOXDIE" that, over a long enough period of time, will cause rapid aging and premature death in the victim. However, FOXDIE causes Liquid Snake to suffer from a fatal heart attack before he can live long enough to see the apparent effects of Werner's Syndrome. Solidus Snake, never having been injected with FOXDIE, but ages naturally, and appears as a middle-aged man in his only appearance in the sequel
''Metal Gear Solid 2: Sons of Liberty''.
See also
References
External links
''This article incorporates public domain text fro
The U.S. National Library of Medicine'
Werner Syndrome from GeneReviews contains extensive information on the disorder
{{DEFAULTSORT:Werner Syndrome
Genodermatoses
Autosomal recessive disorders
Rare diseases
Syndromes affecting the cardiovascular system
DNA replication and repair-deficiency disorders
Progeroid syndromes
Syndromes affecting stature
Syndromes affecting bones
Syndromes affecting the nervous system
Diseases named after discoverers
sv:Progeri#Werners syndrom