TARGETED MUTAGENESIS OF WERNER SYNDROME GENE

描述：沃纳综合征（WS）（“成人早衰症”）是一种罕见的 常染色体隐性遗传性早老性疾病 WS患者表现出普遍的 出现过早衰老，并表现出过早发作的疾病 常见于老年人群，包括双眼白内障， 2型糖尿病、动脉硬化和骨质疏松症。 虽然他们是 易受许多肿瘤的影响，其中包括不成比例的 间叶起源的癌症和相对罕见的肿瘤。 体细胞 表现出加速的复制性衰老和一个突变因子 表型 沃纳综合征基因（WRN）最近已被证明编码解旋酶 与E.杆菌 最初，四个不同的突变， 在日本人和高加索人WS患者中发现了WRN基因。 随后，已经确定了十几种不同的突变。 在本研究中，通过对小鼠进行靶向诱变， 将创建WRN的homolouge。 我们的目标是创造两个模型 自然发生的人类突变，包括常见的日本外显子 删除。 寿命表参数和解剖病理学数据， 强调对肿瘤的频率和频谱的分析， 将在C57 B1/6转基因对照小鼠的整个寿命期间获得。 将从转基因小鼠分离的体细胞的原代培养物进行传代。 用于确定复制寿命、WRN解旋酶活性水平和 HPRT基因座的突变频率。 长期目标是阐明 WS的发病机制和WRN解旋酶在正常衰老中的作用。

DESCRIPTION: The Werner syndrome (WS) ('Progeria of the Adult') is a rare autosomal recessive progeriod disorder. WS patients show a general appearance of premature aging, and exhibit premature onset of disorders commonly seen in the aged population including, bilateral ocular cataracts, type 2 diabetes mellitus, arteriosclerosis and osteoporosis. While they are susceptible to many neoplasms, these include a disproportionate number of cancers of mesenchymal origin and relatively rare neoplasms. Somatic cells from WS patients exhibit accelerated replicative senescence and a mutator phenotype. The Werner syndrome gene (WRN) has recently been shown to encode a helicase homologous to the RecQ of E. coli. Initially, four distinct mutations in the WRN gene were found in Japanese and Caucasian WS patients. Subsequently, more than a dozen different mutations have been identified. In this proposal, animal models of WS by targeted mutagenesis of the murine homolouge of WRN will be created. The goal is to create models of two naturally occurring human mutations, including the common Japanese exonic deletion. Life table parameters and anatomical pathology data, with emphasis upon analysis of the frequencies and the spectrum of neoplasms, will be obtained throughout the lifespan of C57B1/6 transgenic control mice. Primary cultures of somatic cells isolated from the transgenic mice will be used to determine replicative lifespan, WRN helicase activity levels and mutation frequencies at the HPRT locus. The long term goal is to elucidate the pathogenesis of WS and the role of WRN helicase in normal aging.