International Registry of Werner Syndrome

项目摘要 Werner综合征及相关疾病国际登记处（www.example.com） 作为一种资源，以确定和基因型核谱系分离突变负责 Werner综合征（WS）和一系列其他节段性早老样综合征。我们将建立和 冷冻保存来自这些谱系的生物材料，并将其提供给世界各地的研究人员。 我们现在建议进行系统的全基因组搜索，以寻找导致 41例原因不明的早衰症病例，并寻求治疗药物的证据。我们将雇用一名 SNP阵列和下一代测序的组合;这些已经成功地鉴定了新的突变 在少数情况下。这些发现继续支持基因组不稳定性是一个主要的 生物衰老的机制。这些基因座突出了在DNA修复和复制中的主要作用：WRN（DNA 解旋酶/核酸外切酶）、POLD 1（DNA聚合酶δ）和SPRTN（跨损伤DNA的募集 聚合酶）;核结构和染色质相互作用（LMNA）; p53抑制剂（MDM2）; dNTP池（SAMHD 1）;和端粒维持（CTC 1）。 我们还将研究为什么WS表型只在青春期后表现出来。我们假设 可能存在补偿机制的激活，例如其它RecQ解旋酶或DNA修复， 早期发展的道路。为了验证我们的假设，我们将产生人类多能干细胞系， 使用人多能干细胞（hPSC）和CRISPR， 进行转录组研究。分析将集中在这些问题上：其他RecQ解旋酶和DNA 与对照hPSC相比，WS hPSC中表达修复相关基因，这些表达如何变化 分化后;这些表达是否与细胞的表达相关， 衰老基因本项目产生的细胞系和所有可用的患者材料将被制成 提供给其他研究者。

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.