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Gene mutations cause severe kidney dysfunction / Findings lead to improved diagnostics and could enable new therapeutic approaches in the long term

Cystic kidneys are characterized by the formation of fluid-filled cavities that can lead to kidney failure. In addition to impaired kidney function, affected patients often suffer from high blood pressure and liver symptoms. Autosomal Recessive Polycystic Kidney Disease (ARPKD) usually manifests itself at birth or in early childhood and is particularly severe. Researchers at the Medical Center - University of Freiburg, together with German and international colleagues, have now found a cause for the impaired kidney function. The researchers from Germany, Australia, Singapore and the USA recognized that changes in the DZIP1L gene lead to defective cilia function on the kidney cells. Cilia are antenna-shaped projections that regulate important processes for cell division and communication. Disorders of the cilia have long been considered a possible cause of cystic kidneys. The researchers are now hoping to gain more precise information about the processes disrupted in cystic kidneys as a starting point for new therapies. The study was published on May 23, 2017 in the leading journal Nature Genetics.

"Our investigations have shown that more genes are involved in this rather rare form of cystic kidney disease than originally assumed," says study leader Prof. Dr. Carsten Bergmann, a scientist at the Department of Medicine IV (specializing in nephrology and general medicine) at the Medical Center - University of Freiburg and head of the Center for Human Genetics at the laboratory service provider Bioscientia. "This is why patients with cystic kidneys should also be examined for changes in the DZIP1L gene in the future if the previous genetic analyses show no abnormalities," says Prof. Bergmann.

Using new sequencing techniques, the scientists found the changes, known as mutations, in the DZIP1L gene in blood and tissue samples from affected patients. Dr. Elisabeth Ott, Dr. Daniel Epting and Carina Kramer, members of Prof. Bergmann's research group in the Department of Medicine IV at the Medical Center - University of Freiburg, specifically switched off the gene in the zebrafish model organism. As a result, kidney function was impaired. Further cell analyses showed that the antenna-shaped cilia on the kidney cells no longer functioned properly. The researchers also discovered that the DZIP1L gene also plays an important role in the much more common autosomal dominant polycystic kidney disease (ADPKD). This form affects around one to two in every 1,000 people in Germany and more than 12 million patients worldwide.

Based on the current study, the researchers will now continue to investigate the function of DZIP1L in cystic kidneys. The long-term goal is to develop therapies that will make it possible to cure polycystic kidney disease. So far, they can only be treated causally with a kidney transplant.

The study was funded by the German Research Foundation (DFG) and the Federal Ministry of Education and Research (BMBF).

Original title of the publication: Mutations in DZIP1L, which encodes a ciliary transition zone protein, cause autosomal recessive polycystic kidney disease.

DOI: 10.1038/ng.3871

Link to the study: www.nature.com/ng/journal/vaop/ncurrent/full/ng.3871.html

Contact:
Prof. Dr. med. Carsten Bergmann
Study director
Department of Medicine IV (specializing in nephrology and general medicine)
Uniklinik - University of Freiburg
carsten.bergmann@uniklinik-freiburg.de