De Gobbi Marco, Viprakasit Vip, Hughes Jim R, Fisher Chris, Buckle Veronica J, Ayyub Helena, Gibbons Richard J, Vernimmen Douglas, Yoshinaga Yuko, de Jong Pieter, Cheng Jan-Fang, Rubin Edward M, Wood William G, Bowden Don, Higgs Douglas R
Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
Science. 2006 May 26;312(5777):1215-7. doi: 10.1126/science.1126431.
We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder alpha thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream alpha-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.
我们描述了一种遗传性血液疾病α地中海贫血变异形式背后的致病机制。对来自美拉尼西亚的受影响个体进行的关联研究将疾病特征定位到人类16号染色体的端粒区域，该区域包括α珠蛋白基因簇，但通过传统方法未检测到分子缺陷。在对平铺式寡核苷酸阵列进行重测序并结合染色质免疫沉淀和表达分析后，我们在α珠蛋白基因与其上游调控元件之间的非基因区域中鉴定出一个功能获得性调控单核苷酸多态性（rSNP）。该rSNP产生了一个新的启动子样元件，干扰了所有下游α样珠蛋白基因的正常激活。因此，我们的工作阐明了区分中性和功能重要rSNP的策略，同时也确定了一种可能是其他遗传疾病基础的致病机制。
