Kidney disease linked to defects in cells' ability to repair damaged DNA
(Medical Xpress) -- Howard Hughes Medical Institute investigator Friedhelm Hildebrandt has discovered that genetic mutations that impair cells ability to repair damaged DNA can cause chronic kidney disease.
Although chronic kidney disease is a major health burden in the United States, it has no cure. Very little is known about how kidneys fail, Hildebrandt says, and no one understands why the incidence of the disease has been increasing over the past 20 years. Now, Hildebrandt and his colleagues have linked mutations in four different DNA damage repair genes to chronic kidney disease.
Because such mutations increase cells sensitivity to genetic damage, Hildebrandt says the findings suggest that environmental toxins may be contributing to the increased prevalence of kidney disease. Their findings on the first of those genes, FAN1, are described in the August, 2012, issue of the journal Nature Genetics. Their work on the other three genes, MRE11, ZNF423, and CEP164, was reported in Cell on August 3, 2012.
Attempting to answer lingering questions about what causes kidney disease, Hildebrandt has, over the past fifteen years, collected genetic information from more than 5,000 families with childhood kidney disorders. By analyzing that data, his team has discovered that some types of kidney disorders can be caused by mutations in a single gene. Still, most cases of chronic kidney disease remain unexplained.
Four years ago, Hildebrandts lab at the University of Michigan Medical School began to use a new strategy to search for rare mutations associated with chronic kidney disease. Their approach combined two technologies. The first, whole exome sequencing, examines only the part of the genetic sequence that codes for proteins, where most disease-causing mutations occur. By focusing on this area, known as the exome, scientists find mutated genes while avoiding the cost and time of sequencing the remaining 99 percent of the genome.
Many harmless variations exist between the DNA sequences of individuals, so to find the mutations most likely to be causing kidney failure, Hildebrandt followed the sequencing process with a technique called homozygosity mapping. For diseases that are inherited recessively -- meaning they occur only when a mutated copy of the gene is inherited from each parent -- homozygosity mapping identifies disease-causing mutations in populations where genetic diversity is low. Hildebrandt used the mapping data to reduce the number of variations resulting from the exome sequencing data to identify the single gene that causes kidney failure in each individual examined.
It took eight members of Hildebrandts lab more than a year to sift through the genetic sequences of the fifty families in their study. The lab found four mutationsin the genes FAN1, MRE11, ZNF423, and CEP164that were associated with kidney degeneration.
The first mutation that the team investigated, FAN1, appeared in the sequences of two siblings with karyomegalic interstitial nephritis, a disorder featuring early onset kidney failure alongside other cellular abnormalities. To find out if other patients with karyomegalic interstitial nephritis carried the same mutation, Hildebrandt contacted scientists researching the disorder and requested blood samples from affected individuals. After a year of persistent emailing, he was able to screen patients DNA for the FAN1 mutation. In nine out of ten patients, he says, we saw that there were mutations in FAN1.
The FAN1 gene was discovered in 2010 by HHMI investigator Steve Elledges lab at Brigham and Womens Hospital, and found to be involved in repairing damaged DNA.
Using a similar procedure, the team also linked mutations in the CEP164, ZNF423, and MRE11 genes to chronic kidney disease. Surprisingly, Hildebrandt says, all four normally control DNA damage repair. When they tested the function of FAN1, CEP164, and ZNF423 in zebrafish and rats, they found that mutations in any of the four genes impaired cells ability to repair damaged DNA, and also led to kidney degeneration. To further study DNA repair mechanisms they collaborated with Bruce Hamilton at the University of California-San Diego, Rachel Giles at the University of Utrecht and Agata Smogorszewska at Rockefeller University.
The DNA-repair system fixes slipups in the genetic code made during replication or caused by genotoxinsenvironmental factors inflicting damage on genetic material. When the process fails, mutations remain and cells cannot function normally. Defects in DNA damage repair had not previously been associated with chronic kidney disease.
The connection between DNA repair and kidney failure is not yet clear, Hildebrandt says. It can take decades to draw a line from the primary defect to what the disease does to the organism or the human. But he suspects DNA damage that accumulates in the absence of DNA repair leads to cell degeneration. This model may explain chronic organ failure in general, he says, not just in the kidneys. However, the kidneys could be particularly susceptible to DNA degeneration caused by genotoxins, since they process and eliminate many toxins from the body. It could be, Hildebrandt says, that increased exposure to environmental genotoxins has contributed to an increasing incidence of end-stage kidney failure.
Hildebrandt also points out that different mutations of the same DNA-repair gene could cause drastically different conditions. Individuals with mutations that prevent function of the encoded protein entirely would accumulate significant, often fatal damage early in development. Those with less severe mutations, in contrast, would acquire DNA damage more slowly, causing degenerative changes over time.
Hildebrandt says the discovery of this disease mechanism will help in diagnosing kidney failure, which is widespread and often lacks an identified cause. Further, it gives researchers working to develop treatments for chronic kidney disease new clues about where to begin. Thats the hope, says Hildebrandt. That now we might be able to look for drugs that mitigate those effects and or to avoid the genotoxic substances.
Journal reference: Nature Genetics
Provided by Howard Hughes Medical Institute
- Researchers identify new genetic cause for chronic kidney disease Jul 10, 2012 | not rated yet | 0
- Fast-track gene-ID method speeds rare disease search Sep 16, 2010 | not rated yet | 0
- A gene that protects from kidney disease Jul 08, 2007 | not rated yet | 0
- Persons of African and Hispanic heritage at higher risk of chronic kidney disease Jul 15, 2010 | not rated yet | 0
- Gene mutations predict early, severe form of kidney disease Oct 24, 2011 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
Genetics 10 hours ago | 3 / 5 (2) | 0 |
Can human genes be patented? That was the question posed by Alan J. Snyder, vice president and associate provost for research and graduate studies at Lehigh, and Lee Kaplan, scientific director of cellular and molecular genetics ...
Genetics 17 hours ago | 4 / 5 (1) | 0
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
Genetics May 22, 2013 | 4.5 / 5 (4) | 0 |
University of Minnesota Medical School researchers from the Masonic Cancer Center, University of Minnesota, in partnership with the University's Brain Tumor Program, have developed a new mouse model of malignant peripheral ...
Genetics May 20, 2013 | 5 / 5 (1) | 0 |
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
Genetics May 16, 2013 | 3 / 5 (1) | 1 |
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
15 hours ago | 5 / 5 (3) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
12 hours ago | 3.7 / 5 (3) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
13 hours ago | 5 / 5 (4) | 0 |
How can healthy people who hear voices help schizophrenics? Finding the answer for this is at the centre of research conducted at the University of Bergen.
15 hours ago | 4 / 5 (2) | 2
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
9 hours ago | not rated yet | 0
(Medical Xpress)—Patients with diabetes who are depressed are much more likely to develop episodes of dangerously low blood sugars, or hypoglycemia, than are those who are not depressed, a new study has ...
16 hours ago | not rated yet | 0 |