The team of scientists at the European Molecular Biology Laboratory (EMBL) and the University of Michigan discovered that a mutation in the GLIS2 gene causes nephronopthisis (NPHP) in humans and mice. This disease causes the kidney to degenerate and shrink from early childhood, eventually leading to organ failure and often before the age of 30. Currently, the only option is to do a kidney transplant at an early age. However, this latest findings provides drug developers with a new target for effective, non-invasive therapies. Mathias Treier and his group at EMBL developed a new mouse model for NPHP which they have used to shed new light on the disease. "Our mice show striking similarities with NPHP patients," he said. "Very early on in their lives their kidney cells start to die and the mice develop all the characteristic disease symptoms. It is the first time that a mouse model reveals increased cell death as the mechanism underpinning kidney degeneration in NPHP. The genetic cause is a mutation in a gene called GLIS2." GLIS2 normally prevents kidney cell death in adults by shutting down other genes that initiate cell suicide. These death genes are needed during development but a mutation in GLIS2 impairs its function and causes the harmful genes to become reactivated. The end result is that a large number of kidney cells are killed. Then, Friedhelm Hildebrandt and his colleagues at the University of Michigan set about trying to discover if the gene had the same effect in humans. They carried out a genetic screen of NPHP patients and discovered some of them also carried mutations in GLIS2, confirming the gene's important role in the disease. "This is an excellent example of how combining basic research with clinical studies can help uncovering mechanisms of human disease," said Henriette Uhlenhaut who carried out the research in Treier's lab. "The next step will be to translate the insights gained into new therapeutic approaches to develop alternatives to kidney transplantations. With GLIS2 we have already identified one promising candidate drug target and our mouse model will help us find many others." The results are reported in the current online issue of Nature Genetics. The scientists said that the research was needed because mutations in the six known NPHP genes (NPHP1-6) are found in only 35 per cent of cases of nephronopthisis and the disease's mechanism is still unknown. Now that the mechanism by which nephronopthisis kills the kidneys is beginning to unfold, drug developers can start to design drugs to combat its progression.