Kere Juha
Department of Biosciences at Novum, Karolinska Institute, 14157 Huddinge, Sweden.
Philos Trans R Soc Lond B Biol Sci. 2005 Aug 29;360(1460):1551-61. doi: 10.1098/rstb.2005.1684.
Susceptibility genes for complex diseases are characterized by reduced penetrance, caused by the influence of other genes, the environment or stochastic events. Recently, positional cloning efforts have yielded several candidate susceptibility genes in different complex disorders such as Crohn's disease and asthma. Within a genetic locus, however, the identification of the effector gene may pose further challenges and require functional studies. I review two examples of such challenges: the cloning of GPR154 (GPRA) and AAA1 on chromosome 7p14 at a susceptibility locus for atopy and asthma, and the study of HLA-Cw6, CCHCR1 (HCR) and CDSN on chromosome 6p21 at PSORS1, the major susceptibility locus for psoriasis. The susceptibility locus for atopy and asthma contains two genes and only one of them is protein coding. We studied its isoform-specific expression in bronchial biopsies and in a mouse model of ovalbumin-induced inflammation of bronchial epithelia. In the PSORS1 locus, strong linkage disequilibrium between genes has made it difficult to distinguish the effects of the three nearby genes. We engineered transgenic mice with either a HCR non-risk allele or the HCR*WWCC risk allele controlled by the cytokeratin-14 promoter. The results suggested that the overexpression of HCR in mouse skin was insufficient to induce a psoriasiform phenotype, but it appeared to induce allele-specific gene expression changes that were similar to those observed in psoriatic skin.
复杂疾病的易感基因具有外显率降低的特点，这是由其他基因、环境或随机事件的影响所致。最近，定位克隆研究已在不同的复杂疾病（如克罗恩病和哮喘）中发现了多个候选易感基因。然而，在一个基因座内，确定效应基因可能会带来更多挑战，需要进行功能研究。我将回顾此类挑战的两个例子：在7号染色体p14上特应性和哮喘易感基因座处克隆GPR154（GPRA）和AAA1，以及在6号染色体p21上银屑病主要易感基因座PSORS1处研究HLA-Cw6、CCHCR1（HCR）和CDSN。特应性和哮喘的易感基因座包含两个基因，其中只有一个是蛋白质编码基因。我们研究了其在支气管活检组织以及卵清蛋白诱导的支气管上皮炎症小鼠模型中的异构体特异性表达。在PSORS1基因座中，基因之间强烈的连锁不平衡使得区分三个相邻基因的作用变得困难。我们构建了由细胞角蛋白-14启动子控制的带有HCR非风险等位基因或HCR*WWCC风险等位基因的转基因小鼠。结果表明，HCR在小鼠皮肤中的过表达不足以诱导银屑病样表型，但似乎会诱导等位基因特异性的基因表达变化，这与在银屑病皮肤中观察到的变化相似。
