Mouse models of Down syndrome: gene content and consequences.
Mouse models of Down syndrome: gene content and consequences.
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DOI：
10.1007/s00335-016-9661-8
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发表时间：
2016-12
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影响因子：
--
通讯作者：
Gardiner KJ
中科院分区：
文献类型：
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作者：
Gupta M;Dhanasekaran AR;Gardiner KJ
唐氏综合征（Down syndrome，DS）是人类21号染色体三体综合征（human chromosome 21，Hsa 21），是一种具有挑战性的遗传病。它不仅是一个跨越Hsa 21长臂35 Mb的连续基因综合征，而且Hsa 21基因的直系同源物映射到三个小鼠染色体Mmu 16，Mmu 17和Mmu 10的片段。Ts 65 Dn是DS的第一个可行的节段性三体小鼠模型;它是目前在DS认知药物临床前评价中流行的部分三体。Ts 65 Dn的局限性是：（i）对于125种人类蛋白质编码直向同源物，它是三体的，但其中只有90种是Hsa 21直向同源物;以及（ii）对于约75种Hsa 21直向同源物，它缺乏三体性。近年来，已经产生了几种额外的DS小鼠模型，每个三体的Hsa 21基因或其直系同源物的不同子集。为了最好地利用这些模型并解释用它们获得的结果，在提出临床试验之前，有必要了解它们的三体基因内容，相对于完整的21三体。在这里，我们首先回顾Hsa 21蛋白编码基因的功能信息和最近的大量功能RNA基因的注释。然后，我们讨论了Hsa 21同源基因在小鼠基因组中的保守性和基因组分布以及小鼠特异性基因的分布。最后，我们认为DS的小鼠模型的优点和缺点的基础上的Hsa 21的直系同源物的数量和性质，是，不是，在每个三体，并讨论其有效性用于临床前评价药物反应。
Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17 and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are: (i) it is trisomic for 125 human protein coding orthologs, but only 90 of these are Hsa21 orthologs; and (ii) it lacks trisomy for ~75 Hsa21 orthologs. In recent years, several additional mouse models of DS have been generated, each trisomic for a different subset of Hsa21 genes or their orthologs. To best exploit these models and interpret results obtained with them, prior to proposing clinical trials, an understanding of their trisomic gene content, relative to full trisomy 21, is necessary. Here we first review functional information on Hsa21 protein coding genes and the more recent annotation of a large number of functional RNA genes. We then discuss the conservation and genomic distribution of Hsa21 orthologs in the mouse genome and the distribution of mouse-specific genes. Lastly, we consider the strengths and weaknesses of mouse models of DS based on the number and nature of the Hsa21 orthologs that are, and are not, trisomic in each, and discuss their validity for use in preclinical evaluations of drug responses.