Chronic Kidney Disease And Cellular Inability to Repair Damaged DNA
A new study led by Friedhelm Hildebrandt, from the Howard Hughes Medical Institute, shows that chronic kidney disease can be caused by genetic mutations that hinder the ability of the cell to repair the damaged DNA.
Chronic kidney disease is one of the major health problems in the United States, however, a cure for the disease has not yet been discovered. Dr Hildebrandt and his team of scientists have discovered a connection between mutations of four DNA repairing genes and the onset of chronic kidney disease.
Due to the fact that the mutations of these genes causes cells to be more sensitive to genetic damage, the team of researchers suggest that environmental toxins are contributing to the higher prevalence of chronic kidney disease. The findings of the team were published in the journal Nature Genetics and Cell. The four genes discovered to be linked to chronic kidney disease are FAN1, MRE11, ZNF423 and CEP164.
In an attempt to find the causes of kidney disease, Dr Hildebrandt has been gathering genetic information from over 5,000 families for the past 15 years. All of the families had members with kidney disorders beginning in their childhood. After analyzing the gathered data, the research team found that the mutation of a single gene can cause some of the types of kidney disorder. However, most of the chronic kidney disease causes are still unknown.
Several years ago, Dr Hildebrandt started using a new approach for rare mutation searching. This new approach consisted of two technologies. The first technology, called whole exome sequencing, specifically examines the genetic sequence that codes the proteins. Through the use of the whole exome sequencing, scientists avoided the cost and time needed to sequence the rest of the genome.
In order to find the mutations that are more likely to cause kidney failure, Dr Hildebrandt continued the exome sequencing process with a method called homozygosity mapping. For recessively inherited diseases the technique is able to identify the disease-causing mutations. Dr Hildebrandt used this technique in order to reduce the DNA variations that resulted after the exome sequencing, thus being able to identify the single gene that caused kidney failure for each examined patient.
Researchers investigated the genetic sequence of fifty families over the entire course of a year. They found that mutations in four genes – FAN1, MRE11, ZNF423 and CEP164 – were associated with kidney failure.
The first mutation investigated by the researchers team was that of the FAN1 gene. This mutation was found in the exome sequence of two siblings suffering from karyomegalic interstitial nephritis. This disease causes an early onset of kidney failure. In order to find out if karyomegalic interstitial nephritis was caused by the same mutation in other patients as well, Dr Hildebrandt screened their DNA as well. “In nine out of ten patients, we saw that there were mutations in FAN1”, he reported.
The FAN1 gene was first discovered by Steve Elledge in 2010. It was found then that the gene is involved in the repairing of damaged DNA.
The researchers used a similar method to link the mutations in the CEP164, ZNF423 and MRE11 genes to chronic kidney disease. After testing the genes from laboratory rats and zebra-fish, they found that the mutations of these genes led to the inability of the cells to repair damaged DNA. The team led by doctor Hildebrandt also collaborated with Bruce Hamilton, Rachel Giles and Agata Smogorszewska, from the University of California – San Diego, the University of Utrecht and the Rockefeller University, respectively.
The role of the DNA repair system is to fix minor defects that are the result of either replication or environmental factors. The failure of this system leads to abnormalities in cellular function. This is for the first time that the DNA repair mechanism is associated with chronic kidney disease. However, the connection between them is unclear. “It can take decades to draw a line from the primary defect to what the disease does to the organism or the human”, said Dr Hildebrandt, whilst adding that a possible explanation is that DNA damage leads to cellular degeneration. His hypothesis could explain chronic organ failure in general, not just chronic kidney failure.