# International Registry of Werner Syndrome

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $353,419

## Abstract

Project Summary
 The International Registry of Werner Syndrome & Related Disorders (www.wernersyndrome.org)
serves as a resource to ascertain and genotype nuclear pedigrees segregating mutations responsible for
Werner syndrome (WS) and a range of other segmental progeroid syndromes. We shall establish and
cryopreserve biological materials from these pedigrees and provide them to investigators around the world.
 We now propose to conduct systematic genome-wide searches for the gene mutations responsible for
41 progeroid cases with unknown causes and to seek evidence for therapeutic agents. We will employ a
combination of SNP arrays and next generation sequencing; these have successfully identified novel mutations
in a small number of cases. Those findings continue to support the concept of genomic instability as a major
mechanism of biological aging. These loci highlight major roles in DNA repair and replication: WRN (DNA
helicase/exonuclease), POLD1 (DNA polymerase delta), and SPRTN (recruitment of translesional DNA
polymerase); nuclear structure and chromatin interaction (LMNA); an inhibitor of p53 (MDM2); regulation of
dNTP pools (SAMHD1); and telomere maintenance (CTC1).
 We will also investigate why WS phenotypes are manifested only after puberty. We hypothesize that
there may be an activation of compensatory mechanisms such as other RecQ helicases or DNA repair
pathways during early development. To test our hypothesis, we will generate human pluripotent stem cell lines
with and without WRN disease mutations using human pluripotent stem cells (hPSCs) and CRISPR and
conduct transcriptome studies. Analysis will focus on these questions: how other RecQ helicases and DNA
repair related genes are expressed in WS hPSCs compared to control hPSCs, how these expressions change
following differentiation; whether or not these expressions correlated with the expression of cellular
senescence genes. Cell lines generated by this project and all available patient materials will be made
available to other investigators.

## Key facts

- **NIH application ID:** 9904565
- **Project number:** 5R01CA210916-05
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** GEORGE M. MARTIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,419
- **Award type:** 5
- **Project period:** 2016-05-18 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904565

## Citation

> US National Institutes of Health, RePORTER application 9904565, International Registry of Werner Syndrome (5R01CA210916-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9904565. Licensed CC0.

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