Gardiner Katheleen, Costa Alberto C S
Eleanor Roosevelt Institute, University of Denver, 1899 Gaylord Street, Denver, Colorado 80206, USA.
Am J Med Genet C Semin Med Genet. 2006 Aug 15;142C(3):196-205. doi: 10.1002/ajmg.c.30098.
Recent genomic sequence annotation suggests that the long arm of human chromosome 21 encodes more than 400 genes. Because there is no evidence to exclude any significant segment of 21 q from containing genes relevant to the Down syndrome (DS) cognitive phenotype, all genes in this entire set must be considered as candidates. Only a subset, however, is likely to make critical contributions. Determining which these are is both a major focus in biology and a critical step in efficient development of therapeutics. The subtle molecular abnormality in DS, the 50% increase in chromosome 21 gene expression, presents significant challenges for researchers in detection and quantitation. Another challenge is the current limitation in understanding gene functions and in interpreting biological characteristics. Here, we review information on chromosome 21-encoded proteins compiled from the literature and from genomics and proteomics databases. For each protein, we summarize their evolutionary conservation, the complexity of their known protein interactions and their level of expression in brain, and discuss the implications and limitations of these data. For a subset, we discuss neurologically relevant phenotypes of mouse models that include knockouts, mutations, or overexpression. Lastly, we highlight a small number of genes for which recent evidence suggests a function in biochemical/cellular pathways that are relevant to cognition. Until knowledge deficits are overcome, we suggest that effective development of gene-phenotype correlations in DS requires a serious and continuous effort to assimilate broad categories of information on chromosome 21 genes, plus the creation of more versatile mouse models.
近期的基因组序列注释表明，人类21号染色体长臂编码了400多个基因。由于没有证据排除21号染色体长臂的任何重要区段不包含与唐氏综合征（DS）认知表型相关的基因，所以必须将这一整套基因中的所有基因都视为候选基因。然而，可能只有一小部分基因会起关键作用。确定哪些基因是关键基因既是生物学的一个主要研究重点，也是治疗方法有效开发的关键步骤。DS中微妙的分子异常，即21号染色体基因表达增加50%，给研究人员在检测和定量方面带来了重大挑战。另一个挑战是目前在理解基因功能和解释生物学特征方面存在的局限性。在这里，我们综述了从文献以及基因组学和蛋白质组学数据库中收集到的有关21号染色体编码蛋白质的信息。对于每种蛋白质，我们总结了它们的进化保守性、已知蛋白质相互作用的复杂性及其在大脑中的表达水平，并讨论了这些数据的意义和局限性。对于一小部分蛋白质，我们讨论了小鼠模型的神经学相关表型，这些模型包括基因敲除、突变或过表达。最后，我们重点介绍了少数几个基因，最近的证据表明它们在与认知相关的生化/细胞途径中发挥作用。在克服知识缺陷之前，我们认为，要有效地建立DS中的基因-表型相关性，需要认真持续地努力去整合有关21号染色体基因的广泛信息类别，以及创建更多通用的小鼠模型。
