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RegOH's Secondary Sources about Werner Syndrome

 * This article provides an overview of what Werner Syndrome is, what the symptoms are, what causes it, and what other diseases are associated.


 * This article contains more detailed information about the WRN protein.


 * This article gives a good overview of the symptoms and associated disorders of Werner Syndrome. It also discusses the distribution of Werner Syndrome, which has a much higher rate of incidence in Japan than anywhere else.


 * This article provides more information about the Werner Syndrome RecQ helicase.

Emileemagnusen's Secondary Sources about Werner Syndrome

 * This article discusses the clinical features of Werner syndrome and goes into detail about the WRN gene mutation that causes the disease.


 * This article discusses of the complications of Werner Syndrome.


 * This article discusses the relationship between Werner's Syndrome and cancer, another complication of the disease.

Outline
I. Lead

II. Gene
 * a. WRN mutations
 * b. LMNA and atypical Werner Syndrome

III. Effects on Protein structure and function
 * a. RecQ family helicases
 * b. DNA stability

IV. Clinical Symptoms
 * a. physical appearance
 * b. premature aging

V. Treatment and Management

VI. Associated Diseases/Complications
 * a. cancer susceptibility
 * b. diabetes
 * c. osteoporosis

VII. Epidemiology

Preliminary Paragraphs
Lead:

Werner Syndrome (WS), also known as adult progeria, is a rare genetic disorder. It is caused by a mutation in the WRN gene, which encodes proteins that are important for maintaining genetic stability. The mutation often causes chromosomal abnormalities, premature cell aging, and defective DNA replication. Clinically, people with Werner syndrome can develop symptoms of aging as early as the age of 20, including graying of hair, hair loss, bone fragility, as well as other visible signs of aging in the face. Complications and associated comorbities of Werner Syndrome include heart disease, type II diabetes, and cancer. 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. Since then, several other cases of Werner syndrome have been recorded. Many of these cases have occurred in Japan, where a founder effect causes a higher incidence rate than in other populations. The incidence rate of Werner Syndrome 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 Werner syndrome (as of August 2013). The WRN gene, the gene that causes Werner syndrome, was identified in 1996. Prior to 1996, Werner syndrome was thought to be a model for accelerated aging. After discovery of the gene, it became clear the the premature aging displayed in Werner syndrome is not the same, on a cellular level, as normal aging. The role of WRN in DNA repair and it's exonuclease and helicase activities have been the subject of many studies in recent years.

Gene:

The WRN gene is located on the short arm of chromosome 8 and made up of 35 exons. It produces an enzymatic protein that acts as both a helicase, which is important for unwinding DNA, and as a exonuclease, which cleaves nucleotides from a polynucleotide chain. The protein, symbolized as WRNp, contains several functional domains. There are three exonucleus domains in the N-terminus region, seven RecQ DNA helicases in the central region, and a ribonucleas helicase D localized in the C-terminus region. 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 have important implications in the development of Werner Syndrome.

When functioning normally, the WRN gene and associated protein are important for maintaining genome stability. Studies have shown that the WRN protein, which is a RecQ helicase, is involved in DNA replication, recombination, and DNA repair. Specifically, the WRN protein has an important role in responding to replication malfunctions, particularly double stranded breaks, and stalled replication machinery. WRN may reactivate replication by preventing unwanted recombination processes from occuring or by promoting recombination, depending on the type of DNA damage.In addition, the WRN protein physically interacts with or binds to several other proteins that are involved in processing DNA. For example, the WRN protein binds to RPA, which stimilates WRNp's helicase activity. WRNp also physically interacts with p53, a tumor suppresor gene that stops the formation of tumors and the progression of cancers, which inhibits the exonuclease activity of the WRNp.

Loss of the normal functions of the WRN gene and/or protein gives rise to Werner Syndrome. There are currently 35 different known mutations of WRN, which correspond to stop codons, insertions, or deletions that result in a frame-shift mutation. All mutations result in a loss of the C-terminus and the nuclear localization sequence. The inability of the WNR protein to be moved into the nuclei of cells seems to be a critical step in the progression of Werner's Syndrome. The localization of WNRp to the nucleus is exhibited by normally growing cells, while the localization of WRNp outside the nucleus is often seen in arrested cell growth, signifying the importance of the localization sequence in normal genetic stability.

Effects on Cell Structure and Function:

On the molecular level, 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. It is thought that the WRN helicase activity is not only important for DNA repair and recombination, but also for maintating telomere length and stability. Thus, WRN helicase is important for preventing catastrophic telomere loss during DNA replication. In a normal cell, the telomeres, or the ends of chromosomes, undergo repeated shortening during the cell cycle which can prevent the cell from dividing and multiplying. This event can be counteracted by telomerase, an enzyme that extends the ends of the chromosomes by copying the telomeres and synthesizing an indentical, 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 Werner Syndrome, it has yet to be determined if it is the actual cause of the genomic instability observed in cells and high rate of cancer in WS patients.

Without the WRN protein, the interwoven pathways of DNA repair and telomere maintenance fail to surpress cancer and the aging symptoms seen in patients with Werner Syndrome. Events such as rapid telomere shortening cause Werner syndrome cells to exhibit low responses to overall cellular stress. In addition to telomere dysfunction, over-expression of oncogenes and oxidation can induce this type of response. High stress causes a synergistic effect, where Werner Syndrome cells become even more sensitive to agents that increase cell stress and agents that damage DNA. As a result, Werner Syndrome cells show a drastic reduction in replicative lifespan and enter into stage of aging prematurely. The accumulation of these damaged cells due to telomere shortening over many years may be indicative of why Werner Syndrome symptoms only appear after an individual is about twenty years old.

Diagnosis and Clinical symptoms

The WRN mutation that causes Werner syndrome is autosomal and recessive, meaning that Werner Syndrome patients must inherit one copy of the gene from both parents. Patients with Werner syndrome will display rapid premature aging beginning in young adulthood, usually in their early twenties. Diagnosis of Werner syndrome 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. Werner syndrome patients are also generally short statured due to absence of the adolescent growth spurt that usually occurs during puberty, and decreased fertility is seen in patients with Werner syndrome. The most common symptom of Werner syndrome is premature graying and loss of hair. This is also generally the earliest observed symptom of patients with Werner syndrome, with hair loss occurring on the scalp and the eyebrows.

Werner syndrome patients often have skin that appears shiny and tight. The skin may also be thin and hardened. This is due to atrophy of the subcutaneous tissue and dermal fibrosis. Over time, the features of Werner syndrome patients may appear more sharp due to these skin conditions. Other associated skin conditions are very common in Werner syndrome patients, including ulcurs. Ulcers are extremely common and difficult to treat in Werner syndrome patients, and are caused in part by decreased potential of skin cells for replication.

Cataracts are a very common symptom of Werner syndrome. Unlike cataracts associated with normal aging, the cataracts typical in Werner syndrome patients are associated with problems in the lens posterior cortex and subcapsular regions. The cataracts are generally treatable with cataract surgery which should restore normal vision for Werner syndrome patients.

Symptoms of Werner syndrome become apparent in the late teens and early twenties and continue to progress. Most Werner syndrome patients live to about fifty years of age. The most common causes of death for people with Werner syndrome are associated diseases and complications, especially atherosclerosis and and cancer.

Associated Diseases:

Werner syndrome patients are at increased risk for several other diseases, many associated with aging. Atherosclerosis, the thickening of artery walls due to cholesterol buildup, is one very common complication associated with Werner syndrome. While normal Atherosclerosis generally involves the major arteries, smaller arterioles are more likely to be affected in Werner syndrome patients. It is possible that there may be nervous system disorders associated with Werner Syndrome and brain atrophy is present in 40% of Werner syndrome patients. Osteoporosis, the loss of Bone Mineral Density common in post-menopausal women, is a common symptom of Werner syndrome. In contrast with the normal population, the rate of osteoporosis is especially high for male Werner syndrome patients. Diabetes mellitus is another disease that very commonly accompanies Werner syndrome. Skin ulcers in Werner syndrome patients are very common - they occur in about 75% of patients - and can be very severe and difficult to treat. If skin ulcers become badly infected or develop gangrene they often require amputation. Unlike most of the other diseases and complications that commonly occur alongside Werner syndrome, these ulcers are not associated with normal aging in members of the general population.

Werner Syndrome patients are also at an increased risk of cancer, especially malignant melanoma. Soft-tissue sarcomas are the most common types of cancer experienced by Werner syndrome patients. Other types of skin cancer, other epithelial cancers such as thyroid and liver cancers, MDS (Myelodysplastic syndrome), and MFH (malignant fibrous histiocytoma) are also prevalent among Werner syndrome patients. Mutations in the WRN gene, especially single-nucleotide polymorphisms (SNPs) are associated with many of the cancers and other associated diseases of Werner syndrome. WRN SNPs correlate with cancers such as sarcomas and non-Hodgkin lymphomas, as well as diabetes and cardiovascular problems including atherosclerosis.

Proposed additions to WRN gene
RecQ Helicase family

WRN is a member of the RecQ Helicase family. It is the only RecQ Helicase that contains 3' to 5' exonuclease activity which can be useful in repairing DNA damages after replication. These exonuclease activities include degradation of recessed 3' ends and initiation of DNA degradation from a gap in dsDNA. WRN is important in reparation of double stranded breaks, nonhomologous end joining, and base excision repair. WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences.

Post-translational modifications

Phosphorylation of WRN at serine/threonine inhibits helicase and exonuclease activities which are important to post-replication DNA repair. De-phosphorylation at these sites enhances the catalytic activities of WRN. Phosphorylation may affect other post-translational modifications, including sumoylation and acetylation.

Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair.