Werner syndrome
Werner syndrome (progeria) | |
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Werner syndrome has an autosomal recessive pattern of inheritance. | |
Specialty | Endocrinology |
Werner syndrome (WS) or Werner's syndrome, also known as "adult
Werner syndrome is named after the German scientist Otto Werner.[4] He identified the syndrome in four siblings observed with premature aging, which he explored as the subject of his dissertation of 1904.[5]
It has a global incidence rate of less than 1 in 100,000 live births
Presentation
Werner syndrome patients exhibit growth retardation, short stature, premature graying of hair,
Gene expression
Gene
Diagnosis and 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.[16] 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.[17] Patients are generally short-statured due to absence of the adolescent growth spurt. Patients also display decreased fertility.[18] 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.[18]
Werner syndrome patients often have skin that appears shiny and tight, and may also be thin or hardened.[16][18] This is due to atrophy of the subcutaneous tissue and dermal fibrosis.[18] Over time, the characteristic facial features may be more apparent due to these skin conditions. Other associated skin conditions include ulcers,[18] which are very difficult to treat in Werner syndrome patients, and are caused in part by decreased potential of skin cells for replication.[19]
WS
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.[16]
Associated diseases
Werner syndrome patients are at increased risk for several other diseases, many associated with aging.
Patients are also at an increased risk of cancer, especially
Causes
Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the gene,
When functioning normally, the WRN gene and its associated protein (WRNp) are important for maintaining genome stability.
Surprisingly, complete loss of WRN helicase activity does not cause clinical Werner syndrome.[28]
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 (NHEJ).[29] WRN protein also physically interacts with the major NHEJ factor X4L4 (XRCC4-DNA ligase 4 complex).[30] X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.[30]
WRN protein appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks.[29]
WRN protein participates in a complex with RAD51, RAD54, RAD54B and ATR proteins in carrying out the recombination step during inter-strand DNA cross-link repair.[31]
Evidence was presented that WRN protein plays a direct role in the repair of methylation induced DNA damage. This process likely involves the helicase and exonuclease activities of WRN protein that operate together with DNA polymerase beta in long patch base excision repair.[32]
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.
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
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 WS. 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
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, particularly in slowly replicating cells.[41] This finding suggested that WRN may be important in dealing with oxidative DNA damage that underlies normal aging[41] (see DNA damage theory of aging).
Diagnosis
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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
There is evidence that suggests that the
In 2010, vitamin C 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. In addition, it decreases activity of genes activated in human Werner syndrome and increases gene activity involved in tissue repair. Supplementation of vitamin C is suspected to be beneficial in the treatment of human Werner syndrome, although there was no evidence of anti-aging activity in nonmutant mice.[44] In general, treatments are available for only the symptoms or complications and not for the disease itself.[45]
History
Otto Werner was the first to observe Werner syndrome in 1904 as a part of his dissertation research. As a German
Since the initial discovery in 1904, several other cases of Werner syndrome have been recorded. Many of these cases have occurred in Japan, where a founder effect has caused a higher incidence rate than in other populations.[citation needed] 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.[17]
See also
- Accelerated aging disease
- Biogerontology
- Cockayne syndrome
- DNA repair
- Degenerative disease
- Genetic disorder
- Life extension
- Progeria
- Senescence
- Xeroderma pigmentosum
- List of cutaneous conditions
- Progeroid syndrome
References
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External links
This article incorporates public domain text from The U.S. National Library of Medicine
- Werner Syndrome from GeneReviews, contains extensive information on the disorder