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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Resource-Related Research Projects (R24)
Project #
5R24AG042328-03
Application #
8706752
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M1))
Program Officer
Guo, Max
Project Start
2012-08-15
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$200,000
Indirect Cost
$70,550
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Oshima, Junko; Hisama, Fuki M (2014) Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome. Gerontology 60:239-46
Saha, Bidisha; Lessel, Davor; Nampoothiri, Sheela et al. (2013) Ethnic-Specific WRN Mutations in South Asian Werner Syndrome Patients: Potential Founder Effect in Patients with Indian or Pakistani Ancestry. Mol Genet Genomic Med 1:7-14
Tadokoro, Takashi; Rybanska-Spaeder, Ivana; Kulikowicz, Tomasz et al. (2013) Functional deficit associated with a missense Werner syndrome mutation. DNA Repair (Amst) 12:414-21