U.S. Department of Health and Human Services

Defective DNA Repair and Chronic Kidney Disease

Mutations in a protein that is part of the cellular machinery that helps maintain the genome and repair DNA damage might contribute to chronic kidney disease, as well as to a rare cystic kidney disease called nephronophthisis (NPHP)-like ciliopathy. 

In a recent report, scientists identified mutations in the gene that encodes the FAN1 protein as a cause of karyomegalic interstitial nephritis (KIN), a rare and slowly progressive chronic kidney disease marked by fibrosis and cells with massively enlarged cell nuclei. The FAN1 protein is part of a multi-protein complex that works to repair damage to DNA, which is contained in the cell nucleus. Specifically, this complex breaks the inappropriate chemical bonds that sometimes link one chromosome to another. These inter-chromosomal cross-links can form following exposure to toxins, or as a result of normal metabolism and aging. Such cross-links, if not repaired, can cause enlarged nuclei, prevent gene activation and cell division, and ultimately lead to cell death. 

The scientists showed that FAN1 mutants had an impaired ability to remove DNA cross-links in patients with KIN, and suggested that this diminished capacity to repair DNA damage was an important factor in progressive kidney disease. Evidence for the key role of FAN1 was also seen in animal studies. In the zebrafish, lower levels of FAN1 caused a defect similar to KIN, with diminished DNA repair, cell death, and kidney cysts. 

Further support for the importance of DNA repair was observed in a well-characterized rat model of kidney disease arising from high blood pressure, in which the extent of DNA damage in the kidney was correlated with kidney failure. This observation supports the hypothesis that faulty DNA repair may be an important underlying cause of kidney disease arising from various causes. 

DNA damage has been shown to be associated with exposure to toxins, and the kidney—as an organ whose primary function is to remove waste products from the blood—is likely exposed to levels of toxic agents that are higher than those in most other organs. This study identifies defective repair of DNA damage in the kidney—and the accumulation of this damage, subsequent cell dysfunction, and cell death—as an important cause of fibrosis and subsequent loss of kidney function in patients with KIN. As fibrosis similar to that seen in KIN is a feature seen in chronic kidney disease in general, the role of DNA damage and repair in other forms of kidney disease may prove to have wider applicability. Indeed, future research could explore whether these findings may be relevant to many diseases in which fibrosis is a hallmark.

Zhou W, Otto EA, Cluckey A, et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet 44: 910-915, 2012.

 

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