Modeling neuropsychiatric disease-relevant human SNPs in mice.
Modeling neuropsychiatric disease-relevant human SNPs in mice.
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在小鼠中模拟神经精神疾病相关的人类 SNP。
DOI：
10.1038/npp.2010.143
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Blendy,JulieA
中科院分区：
文献类型：
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作者：
Blendy,JulieA
单核苷酸多态性（SNP）是当基因组中的单个核苷酸改变时发生的DNA序列的变异。这些看似微小的变化可能对人类如何应对疾病，环境和药物产生重大影响。小鼠中的基因靶向允许分析哺乳动物中基因功能的各个方面。在过去的十年中，数以千计的零，亚纯型和条件等位基因已被构建。基因靶向也可用于在小鼠中产生其中已鉴定人类SNP的那些基因的点突变。然而，这种方法尚未被广泛使用，部分原因是构建所需的复杂靶向载体涉及的劳动密集型程序。细菌人工染色体载体的“重组工程”的最新进展已经简化了该过程（Yu等人，2000; Lee等人，2001），使得“敲入”小鼠的使用成为开发小鼠模型以研究人类疾病相关SNP的自然进展。神经精神疾病依赖于多种遗传和环境决定因素，因此代表了动物建模的一些最大挑战。然而，一些携带特定SNP的基因已经成为有希望的候选者。其中，脑源性神经营养因子（Bdnf）、μ-阿片受体（Oprm 1）和儿茶酚-O-甲基转移酶（COMT）中常见的SNP已在小鼠中使用三种独特的方法建模。BDNF基因中常见的SNP（Val 66 Met）与人类的解剖学（海马体积）和行为学（记忆任务中的表现）损伤相关。为了概括小鼠中的等效变体，我们进行了点突变（G196 A）以将缬氨酸66变为甲硫氨酸。除了预期的海马体积减少和背景依赖记忆受损的表型外，这些小鼠还揭示了一种新的焦虑表型，这在人类中尚未报道
Single nucleotide polymorphisms (SNPs) are variations in DNA sequence that occur when a single nucleotide in the genome is altered. These seemingly small variations can have a major impact on how humans respond to disease, environment, and drugs. Gene targeting in mice has allowed the analysis of varied aspects of gene function in mammals. During the past decade, thousands of null, hypomorphic, and conditional alleles have been constructed. Gene targeting can also be used to generate point mutations in mice for those genes in which human SNPs have been identified. This approach, however, has not yet been widely used due, in part, to the laborintensive procedures involved in building the complex targeting vectors required. Recent advances in ‘recombineering’of bacterial artificial chromosome vectors have streamlined this process (Yu et al, 2000; Lee et al, 2001), making the use of ‘knock-in’mice a natural progression for the development of mouse models to investigate human disease-related SNPs. Neuropsychiatric diseases are dependent on multiple genetic and environmental determinants, and thus represent some of the greatest challenges for animal modeling. However, a few genes harboring specific SNPs have emerged as promising candidates. Among these, common SNPs in brainderived neurotrophic factor (Bdnf), the μ-opioid receptor (Oprm1), and catechol-O-methyltransferase (COMT) have been modeled in mice using three unique approaches.A common SNP in the BDNF gene (Val66Met) is associated with anatomical (hippocampal volume) and behavioral (performance in memory tasks) impairments in humans. To recapitulate the equivalent variant in mice, we made a point mutation (G196A) to change valine 66 to methionine. In addition to the expected phenotypes of decreased hippocampal volume and impaired context-dependent memory, these mice revealed a novel anxiety phenotype that had not yet been reported in humans