The production of transgenic mice expressing human cystathionine beta-synthase to study Down syndrome
The production of transgenic mice expressing human cystathionine beta-synthase to study Down syndrome
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DOI：
10.1007/s10519-006-9046-y
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发表时间：
2006-05-01
影响因子：
2.6
通讯作者：
Patterson, David
中科院分区：
文献类型：
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作者：
Butler, Christine;Knox, Aaron J.;Patterson, David
唐氏综合症（DS）是严重认知障碍的最常见遗传原因。我们假设，通过识别与认知障碍相关的代谢改变，可能有可能开发医学或饮食干预来改善退行性痴呆患者的认知障碍。有证据表明，一碳/转硫（1C-TS）代谢在DS患者中是异常的。胱硫氨酸-合成酶（CBS）在这一代谢系统中起着关键作用。CBS的基因位于人类第21号染色体上，有证据表明，患有DS的个体的组织和细胞中CBS酶活性升高。为了分析CBS在唐氏综合症中可能的作用，我们生产了几系表达人类CBS基因的转基因小鼠。我们描述了使用荧光原位杂交（FISH）分析来表征每条线的转基因插入位点。我们通过RT-PCR对每个转基因品系的初步表达分析表明，这些小鼠中人类CBS mRNA水平的组织特异性可能与同一动物中小鼠CBS mRNA水平的组织特异性不同。这些小鼠对于评估CBS基因的调控和CBS在认知中的作用将是无价的。它们还可用于开发针对1C-TS代谢异常的治疗方法，以改善DS患者的认知能力。
Down syndrome (DS) is the most common genetic cause of significant cognitive disability. We hypothesize that by identifying metabolic alterations associated with cognitive impairment, it may be possible to develop medical or dietary interventions to ameliorate cognitive disabilities in persons with DS. Evidence suggests that one-carbon/transsulfuration (1C-TS) metabolism is abnormal in persons with DS. Cystathionine beta-synthase (CBS) plays a critical role in this metabolic system. The gene for CBS is on human chromosome 21, and there is evidence of elevated CBS enzyme activity in tissues and cells from individuals with DS. To analyze the possible role of CBS in Down syndrome, we have produced several lines of transgenic mice expressing the human CBS gene. We describe the use of Florescence Situ Hybridization (FISH) analysis to characterize the transgene insertion site for each line. Our initial expression analysis of each transgenic line by RT-PCR shows that the tissue specificity of human CBS mRNA levels in these mice may differ from the tissue specificity of mouse CBS mRNA levels in the same animals. These mice will be invaluable for assessing the regulation of the CBS gene and the role of CBS in cognition. They can also be used to develop therapies that target abnormalities in 1C-TS metabolism to improve cognition in persons with DS.