Werner syndrome (WS) is the prototypic segmental progeroid syndrome. Started in 1988, the International Registry of Werner Syndrome has served as a resource to ascertain and genotype WS pedigrees, establish and cryopreserve biological materials from these pedigrees and provide these materials to investigators around the world. We also provide public information about WS to clinicians and to the general public. This network of resources led to the discovery of the WRN gene responsible for classical WS as well as novel LMNA mutations among patients with atypical Werner syndrome (AWS). As requested by the Japanese Werner Consortium (P.I. Koutaro Yokote, Chiba University, Japan), we assist in their nation-wide survey of WS and in collaborative epidemiological studies to evaluate the phenotypes of heterozygous carriers of WRN mutations (Keitaro Matsuo, Aichi Cancer Center Research Institute, Japan). The Registry has evolved to accept cases with a broader range of progeroid phenotypes in order to facilitate the discovery of new biochemical genetic pathways with the potential to modulate mechanisms of intrinsic biological aging. Examples include HapMap linkage analysis (P.I. Christian Kubisch, University of Ulm, Germany) and whole exome sequencing (P.I. Deborah Nickerson, University of Washington). We now propose to expand the scope of our Werner Registry to seek evidence for alleles at WRN and other loci that are associated with unusually enhanced functions. We will bring together two heretofore rather separate gerontologic communities: our colleagues who focus on deleterious mutations associated with progeroid syndromes and those interested in the genetic basis of unusually successful aging (Thomas Perls, Boston University, Nir Barzilai, Albert Einstein College of Medicine). The initial focus is to elucidate the functional significance of WRN SNPs in coding areas and putative cis-regulatory domains associated with exceptional longevity (Akira Yasui, Tohoku University, Japan;Lawrence A. Loeb, University of Washington). These studies will be extended to other relevant loci, including LMNA and newly identified AWS genes.

Public Health Relevance

The International Registry of Werner Syndrome provides biological materials, clinical data and educational resources to the scientific community. Our long term goal is to facilitate research on genetic modulations of human healthspan and lifespan. In the present application, we shall expand our network to include investigations of alleles with enhanced functions as well as diminished functions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Resource-Related Research Projects (R24)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M1))
Program Officer
Guo, Max
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code
Theda, Lindsey; Drews, Michelle K; Zitnik, Galynn et al. (2016) Aβ 1-40 enhances the proliferation of human diploid fibroblasts. Neurobiol Aging 38:11-3
Tokita, Mari; Kennedy, Scott R; Risques, Rosa Ana et al. (2016) Werner syndrome through the lens of tissue and tumour genomics. Sci Rep 6:32038
Hisama, Fuki M; Oshima, Junko; Martin, George M (2016) How Research on Human Progeroid and Antigeroid Syndromes Can Contribute to the Longevity Dividend Initiative. Cold Spring Harb Perspect Med 6:a025882
Barthélémy, Florian; Navarro, Claire; Fayek, Racha et al. (2015) Truncated prelamin A expression in HGPS-like patients: a transcriptional study. Eur J Hum Genet 23:1051-61
Lessel, Davor; Hisama, Fuki M; Szakszon, Katalin et al. (2015) POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome. Hum Mutat 36:1070-9
Hisama, Fuki M; Kubisch, Christian; Martin, George M et al. (2015) Clinical utility gene card for: Werner Syndrome--Update 2014. Eur J Hum Genet 23:
Lessel, Davor; Vaz, Bruno; Halder, Swagata et al. (2014) Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet 46:1239-44
Oshima, Junko; Hisama, Fuki M; Martin, George M (2014) An encouraging progress report on the treatment of progeria and its implications for atherogenesis. Circulation 130:4-6
Lessel, Davor; Saha, Bidisha; Hisama, Fuki et al. (2014) Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier? Am J Med Genet A 164A:2510-3
Saha, Bidisha; Cypro, Alexander; Martin, George M et al. (2014) Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN-deficient human fibroblasts. Aging Cell 13:573-5

Showing the most recent 10 out of 20 publications