A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and Angelman syndromes
A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and Angelman syndromes
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DOI：
10.1073/pnas.96.16.9258
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发表时间：
1999-08-03
影响因子：
11.1
通讯作者：
Nicholls, RD
中科院分区：
文献类型：
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作者：
Gabriel, JM;Merchant, M;Nicholls, RD
Prader-Willi综合征（PWS）和Angelman综合征（AS）是由于人类15q11-q13染色体上的印迹基因功能丧失而引起的。小鼠7号染色体的中心部分与人类15q11-q13染色体同源，基因顺序和印迹特征都保持不变。我们在这里报道了一个转基因插入（爱泼斯坦-巴尔病毒潜伏膜蛋白2A， LMP2A）到小鼠染色体7C的特性，这导致小鼠PWS和AS模型依赖于传递亲本的性别。表观基因型（等位基因表达和DNA甲基化）和荧光原位杂交分析表明，转基因诱导的突变产生了PWS/ as同源区域的完全缺失，但没有缺失侧翼位点。由于完整的7号染色体与缺失的同系物相反，在PWS和AS小鼠的体细胞中维持了正确的印记，并在AS小鼠的雌雄生殖细胞中建立了正确的印记，因此同源关联和复制异步不属于印记机制的一部分。这种遗传缺失小鼠模型将对PWS的病因基因和机制的鉴定、表型基础和治疗方法的研究特别有用。
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) result from the loss of function of imprinted genes in human chromosome 15q11-q13, The central part of mouse chromosome 7 is homologous to human 15q11-q13, with conservation of both gene order and imprinted features. We report here the characterization of a transgene insertion (Epstein-Barr virus Latent Membrane Protein 2A, LMP2A) into mouse chromosome 7C, which has resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicate that the transgene-induced mutation has generated a complete deletion of the PWS/AS-homologous region but has not deleted flanking loci. Because the intact chromosome 7, opposite the deleted homolog, maintains the correct imprint in somatic cells of PWS and AS mice and establishes the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism. This heritable-deletion mouse model will be particularly useful for the identification of the etiological genes and mechanisms, phenotypic basis, and investigation of therapeutic approaches for PWS.