Characterization of novel single gene causes of nephrotic syndrome in Drosophila

激素抵抗型肾病综合征是慢性肾脏疾病的常见原因，目前尚缺乏根治疗法。在很大一部分病例中，病因是遗传的。在希尔德布兰特实验室(波士顿儿童S医院/哈佛医学院)的主要贡献下，已经确定了30多种单遗传学原因。在另外19个基因中，发现了数量不足的受影响家庭，因此目前的数据还不够充分。然而，单基因疾病中的突变通常很少见，其中几个基因很可能在肾病综合征的发病机制中发挥作用。最近的发现表明，果蝇肾细胞和肾小球滤过器之间有惊人的相似之处。这使得在果蝇模型中分析这些疾病基因成为可能。肾细胞的内吞活性可以通过摄取荧光标记的大分子来观察，如德克萨斯-红-亲和素。这将呈现与狭缝隔膜相对应的肾细胞隔膜的状态信息。因此，在肾细胞中定向RNAi表达可以筛选出19个人类基因中的16个的果蝇同源基因。一个或几个已证实的基因的功能可以在果蝇身上得到更详细的描述。果蝇中广泛的遗传工具可以用来达到这一目的。最后，可以通过对小鼠模型的聚焦分析来验证研究结果。这些努力很有可能为肾病综合征的发病机制提供新的见解。

Steroid-resistant nephrotic syndrome is a frequent cause of chronic kidney disease and curative treatment is lacking. In a large proportion of cases the etiology is genetic. More than 30 monogenetic causes have been identified with a major contribution from the Hildebrandt lab (Boston Children´s Hospital/Harvard Medical School). In another 19 genes an insufficient number of affected families have been found, so the data are currently insufficient. However, mutations in single gene disorders are commonly rare and several of these genes most likely play a role in the pathogenesis of nephrotic syndrome. Recent findings indicate a surprising similarity between the Drosophila Nephrocyte and the glomerular filtration apparatus. This allows an analysis of such disease genes in the Drosophila model. The endocytic activity of Nephrocytes can be visulized by the uptake of fluorescently labelled macromolecules like Texas-Red-Avidin. This renders information about the state of the Nephrocyte diaphragm that corresponds to the slit diaphragm. Directed RNAi-expression in Nephrocytes thus allows screening of the Drosophila Homologs available for 16 of the 19 human genes. The function of one or several of the confirmed genes could be characterized in more detail in Drosophila. The wide array of genetic tools in Drosophila could be employed to this end. Finally, findings could be verified by focused analysis in the mouse model. These efforts will most likely deliver new insight into the pathgenesis of nephrotic syndrome.