Werner syndrome

Werner syndrome has an autosomal recessive pattern of inheritance.

Werner syndrome (WS), also known as "adult progeria",^[1]:573 is a rare, autosomal recessive^[2][3][4] progeroid syndrome (PS), which is characterized by the appearance of premature aging.^[5]

Werner syndrome is named after the German scientist Otto Werner.^[6] He identified the syndrome in four siblings observed with premature aging, which he explored as the subject of his dissertation of 1904.^[7]

It has a global incidence rate of less than 1 in 100,000 per live birth^[3] (although incidence in Japan and Sardinia is higher, affecting 1 in 20,000-40,000 and 1 in 50,000, respectively);^[8][9] there have been 1,300 reported cases.^[10] Affected individuals typically grow and develop normally until puberty; the mean age of diagnosis is twenty-four, often realized when the adolescent growth spurt is not observed.^[11] The youngest person diagnosed was six years old.^[12] The median and mean age of death is 47-48 and 54 years, respectively;^[13] the main cause of death is cardiovascular disease or cancer.^[10][11]

Characteristics

The appearance of affected individuals is abnormal. They exhibit growth retardation, short stature, premature graying of hair, alopecia (hair loss), wrinkling, prematurely aged face with a beaked nose, skin atrophy (wasting away) with scleroderma-like lesions, lipodystrophy (loss of fat tissues), abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli (around ankles). Other medical signs include change in voice (weak, hoarse, high-pitched), atrophy of gonads leading to reduced fertility, bilateral cataract (clouding of lens), premature arteriosclerosis (thickening and loss of elasticity of arteries), calcinosis (calcium deposits in blood vessels), atherosclerosis (blockage of blood vessels), type 2 diabetes, osteoporosis (loss of bone mass), telangiectasia, and malignancies.^[3][10] In fact, the prevalence of rare cancers, such as meningiomas, are increased in individuals with Werner syndrome.^[14]

Causes

Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the eponymous gene, WRN; the only gene currently attributed to cause Werner syndrome.^[12][13] WRN, which lies on chromosome 8 in humans,^[15] encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication.^[4][8] Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.

Mutations which cause Werner syndrome all occur at the regions of the gene which encode for protein, and not at non-coding regions.^[16] These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (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.^[16] Furthermore, mutated proteins are more likely to be degraded than normal WRNp.^[8] 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 increase the survival of these disfunctional cells.^[17]

Cells of affected individuals have reduced lifespan in culture,^[18] have more chromosome breaks and translocations^[19] and extensive deletions.^[20] These mutations may in turn cause more RecQ-independent aging phenotypes.

Molecular cellular biology

The WRNp protein have been shown to be associated with RAD52 (a recombination mediator protein),^[21] the Ku complex,^[22] components of the DNA replication complex (DNA polymerase,^[23][24] human replication protein A,^[25] proliferating cell nuclear antigen^[26] and topoisomerase I),^[26] p53,^[27] and TRF2 (a telomeric repeat binding factor).^[28]

Treatment

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. Vitamin C decreases activity of genes activated in human Werner syndrome, and increases gene activity involved in tissue repair.^[29] Vitamin C supplementation is suspected to be beneficial in the treatment of human Werner syndrome, although there was no evidence of anti-aging activity in nonmutant mice.^[29]

Popular culture

On the episode "Stargazer in a Puddle" from the series Bones, the victim had Werner syndrome.

Werner syndrome was featured in the film Jack, starring Robin Williams, in which his character aged four times faster than normal.

In an early cut scene from the game Metal Gear Solid 4, Otacon cites "classic Werner syndrome" as the most likely cause of Solid Snake's premature aging, though he goes on to say that testing had been inconclusive. It is later said that Solid Snake's body was designed to break down quickly through fictional man made "terminator genes".

In season 3 episode 9, "The Ballad of Kevin and Tess", of TV show The 4400, Kevin is said to have Werner syndrome to hide his real condition from the public.

In The Invisible Man (2000 TV series) season 1 episode 6, "Impetus", the new character Gloria has an experimentally altered type of Werner syndrome that causes it to become contagious.

The central character in Gail Tsukiyama's novel DREAMING WATER (2002) has Werner's Syndrome.

See also

References

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
• Werner syndrome at libero.it
• DNA Repair at rcn.com
• Segmental Progeria at benbest.com
• WRN at the GenAge database.
• werner at NIH/UW GeneTests
• 00421 at CHORUS
• Cancer.Net: Werner Syndrome