Werner Syndrome 

  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: May 27, 2011
 

Background

Otto Werner originally defined Werner syndrome (WS) in 1904 on the basis of sclerodermalike, thin, tight skin and bilateral cataracts. WS is also known as progeria adultorum, progeria of the adult, and pangeria. WS is the most common of the premature aging disorders. Progeria can also refer to Hutchinson-Gilford syndrome, which is described as a lamin A gene defect and has onset early in life. The term progeria is derived from a Greek term meaning "before old age." See the images below.

Werner syndrome. Werner syndrome. Werner syndrome. Werner syndrome.

The aging process involves increasing errors in the mitotic machinery of dividing cells in the postreproductive stage of life; therefore, WS serves as a model for studying the aging process in vivo and in vitro.[1] However, many organs in patients with WS prematurely undergo changes that are usually associated with aging. No mental retardation is observed.

WS is a premature aging disorder that may serve as a model of normal human aging.[2] In vivo aging is linked with accelerated aging of fibroblasts in culture, possibly due to the genomic instability, a hallmark of WS. Genome instability activates stress kinases, implying that kinase inhibitors may form the basis of antiaging therapies for individuals with WS.

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Pathophysiology

Werner syndrome (WS) is an autosomal recessive disorder that affects connective tissue throughout the body. This segmental progeroid syndrome is caused by null mutations at the WRN locus,[3] which codes for a member of the RecQ family of DNA helicases. Enzymes in this group unwind double helix RNA and DNA. The protein is likely to be involved in the response to DNA damage during replication, as well as in the replication and transcription processes. The disease is connected with excessive synthesis of collagen types I and III, which is dependent on elevated messenger RNA (mRNA) levels.

The collagenase level is also increased several times. However, a child may have characteristics of WS but with no identifiable mutation in the WRN gene. Such cases are classified as atypical WS.[4] A paper from 2010 reported 18 new mutations, including 2 genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and 2 rare missense mutations.[5]

WS have been classified is a member of the RecQ family of DNA helicases implicated in the resolution of DNA structures leading to the stall of replication forks.[6] Fragile sites may be DNA regions particularly sensitive to replicative stress. Evidence was recently presented of a crucial role for a helicase in protecting cells against chromosome breakage at normally occurring replication fork-stalling sites.

Human progeroid syndromes are linked with mutations in single genes accelerating some, but not all, features of normal aging.[7] Most are associated with defects in genome maintenance.

LMNA (lamin A/C) gene mutation has been described with atypical Werner syndrome, with the severe metabolic complications, the extent of the lipodystrophy being linked with A133L mutation in the LMNA gene.[8]

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Epidemiology

Frequency

United States

WS is a rare disorder. The estimated incidence is 1 case in 1 million individuals.

International

WS is more common in Japan and Sardinia than in other regions. About 1000 cases are reported in the world; more than 800 of these cases are in Japan.

Mortality/Morbidity

  • The mean survival for patients with WS is 46 years.
  • Death usually occurs when patients are aged 30-50 years because of atherosclerosis or malignant tumors.

Race

No racial predilection is reported.

Sex

Both sexes are affected equally.

Age

The onset of WS might occur in individuals in their mid teens, or it may be delayed until an individual is as old as 30 years. The average age of patients at the time of diagnosis is 37 years.

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Contributor Information and Disclosures
Author

Camila K Janniger, MD  Clinical Professor of Dermatology, Clinical Associate Professor of Pediatrics, Chief of Pediatric Dermatology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Camila K Janniger, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Anna Wozniacka, MD, PhD  Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland

Anna Wozniacka, MD, PhD is a member of the following medical societies: European Academy of Dermatology and Venereology

Disclosure: Nothing to disclose.

Specialty Editor Board

Franklin Flowers, MD  Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, Affiliate Associate Professor of Pediatrics and Pathology, University of Florida College of Medicine

Franklin Flowers, MD, is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology

Disclosure: Nothing to disclose.

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Glen H Crawford, MD  Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Department of Dermatology, Geisinger Medical Center

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. Nehlin JO, Skovgaard GL, Bohr VA. The Werner syndrome. A model for the study of human aging. Ann N Y Acad Sci. Jun 2000;908:167-79. [Medline].

  2. Davis T, Wyllie FS, Rokicki MJ, Bagley MC, Kipling D. The role of cellular senescence in Werner syndrome: toward therapeutic intervention in human premature aging. Ann N Y Acad Sci. Apr 2007;1100:455-69. [Medline].

  3. Zhao N, Hao F, Qu T, Zuo YG, Wang BX. A novel mutation of the WRN gene in a Chinese patient with Werner syndrome. Clin Exp Dermatol. May 2008;33(3):278-81. [Medline].

  4. Barrios Sanjuanelo A, Munoz Otero C. [Atypical Werner syndrome: Atypical progeroid syndrome: A case report.]. An Pediatr (Barc). May 7 2010;[Medline].

  5. Friedrich K, Lee L, Leistritz DF, et al. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet. May 5 2010;[Medline].

  6. Pirzio LM, Pichierri P, Bignami M, Franchitto A. Werner syndrome helicase activity is essential in maintaining fragile site stability. J Cell Biol. Jan 28 2008;180(2):305-14. [Medline].

  7. Kyng KJ, Bohr VA. Gene expression and DNA repair in progeroid syndromes and human aging. Ageing Res Rev. Nov 2005;4(4):579-602. [Medline].

  8. Doh YJ, Kim HK, Jung ED, Choi SH, Kim JG, Kim BW, et al. Novel LMNA gene mutation in a patient with Atypical Werner's Syndrome. Korean J Intern Med. Mar 2009;24(1):68-72. [Medline].

  9. Massip L, Garand C, Paquet ER, et al. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J. Jan 2010;24(1):158-72. [Medline].

  10. Solek-Pastuszka J, Zagrodnik-Ulan E, Plonka T, et al. Pregnancy complicated by Werner syndrome. Acta Obstet Gynecol Scand. Feb 2011;90(2):201-2. [Medline].

  11. Wang Z, Xu Y, Tang J, Ma H, Qin J, Lu C, et al. A polymorphism in Werner syndrome gene is associated with breast cancer susceptibility in Chinese women. Breast Cancer Res Treat. Feb 10 2009;[Medline].

  12. Ariyoshi K, Suzuki K, Goto M, Watanabe M, Kodama S. Increased Chromosome Instability and Accumulation of DNA Double-strand Breaks in Werner Syndrome Cells. J Radiat Res (Tokyo). May 2007;48(3):219-31. [Medline].

  13. Barak Y, Sirota P, Kimhi R, Slor H. Werner's syndrome (adult progeria): an affected mother and son presenting with resistant psychosis. Compr Psychiatry. Nov-Dec 2001;42(6):508-10. [Medline].

  14. Bohr VA, Souza Pinto N, Nyaga SG, Dianov G, Kraemer K, Seidman MM, et al. DNA repair and mutagenesis in Werner syndrome. Environ Mol Mutagen. 2001;38(2-3):227-34. [Medline].

  15. Brosh RM Jr, Bohr VA. Roles of the Werner syndrome protein in pathways required for maintenance of genome stability. Exp Gerontol. Apr 2002;37(4):491-506. [Medline].

  16. Fossel M. Human aging and progeria. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1477-81. [Medline].

  17. Harrigan JA, Wilson DM, Prasad R, Opresko PL, Beck G, May A, et al. The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta. Nucleic Acids Res. Jan 30 2006;34(2):745-54. [Medline].

  18. Hrabko RP, Milgrom H, Schwartz RA. Werner's syndrome with associated malignant neoplasms. Arch Dermatol. Feb 1982;118(2):106-8. [Medline].

  19. Ishikawa Y, Miller RW, Machinami R, Sugano H, Goto M. Atypical osteosarcomas in Werner Syndrome (adult progeria). Jpn J Cancer Res. Dec 2000;91(12):1345-9. [Medline].

  20. Machwe A, Xiao L, Orren DK. Length-dependent degradation of single-stranded 3' ends by the Werner syndrome protein (WRN): implications for spatial orientation and coordinated 3' to 5' movement of its ATPase/helicase and exonuclease domains. BMC Mol Biol. 2006;7:6. [Medline].

  21. Navarro CL, Cau P, Levy N. Molecular bases of progeroid syndromes. Hum Mol Genet. Oct 15 2006;15 Spec No 2:R151-61. [Medline].

  22. Opresko PL, Laine JP, Brosh RM Jr, Seidman MM, Bohr VA. Coordinate action of the helicase and 3' to 5' exonuclease of Werner syndrome protein. J Biol Chem. Nov 30 2001;276(48):44677-87. [Medline].

  23. Oshima J. The Werner syndrome protein: an update. Bioessays. Oct 2000;22(10):894-901. [Medline].

  24. Shibuya H, Kato A, Kai N, Fujiwara S, Goto M. A case of Werner syndrome with three primary lesions of malignant melanoma. J Dermatol. Sep 2005;32(9):737-44. [Medline].

 
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