Characterization of novel single gene causes of nephrotic syndrome in Drosophila

类固醇抵抗性肾病综合征是慢性肾脏疾病的常见病因，缺乏根治性治疗。在很大一部分病例中，病因是遗传的。在Hildebrandt实验室（波士顿儿童医院/哈佛医学院）的主要贡献下，已经确定了30多种单基因原因。在另外19个基因中，发现的受影响家族数量不足，因此目前的数据不足。然而，单基因疾病的突变通常是罕见的，其中一些基因很可能在肾病综合征的发病机制中起作用。最近的研究结果表明果蝇肾细胞和肾小球滤过器之间有惊人的相似性。这允许在果蝇模型中分析这种疾病基因。肾细胞的内吞活性可以通过摄取荧光标记的大分子（如Texas-Red-Avidin）来观察。这显示了肾细胞隔膜与狭缝隔膜相对应的状态信息。因此，肾细胞中的定向rnai表达允许筛选19个人类基因中的16个果蝇同源物。一个或几个已确认的基因的功能可以在果蝇中更详细地表征。果蝇中广泛的遗传工具可以用于这一目的。最后，通过小鼠模型的集中分析验证了研究结果。这些努力将最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.