Characterization of novel single gene causes of nephrotic syndrome in Drosophila

• Applicant: Privatdozent Dr. Tobias Hermle
• Subject Area: Nephrology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277333950

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Friedhelm Hildebrandt