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DNA Damage Found in Patients with Friedreich's Ataxia

By Ed Kang
February 2010

Ben Van Houten
Former NIEHS Senior Investigator and Program Analysis Branch Chief Ben Van Houten, above,  is the Richard M. Cyert Professor of Molecular Oncology and leader of the molecular and cellular cancer biology program at UPCI, and professor, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine. (Photo courtesy of Steve McCaw)

Even after moving into an administrative role in the NIEHS Division of Extramural Research and Training, Haugen maintained her scientific interest in gene expression analysis. (Photo courtesy of Steve McCaw)

An NIEHS/NIH-funded team of investigators published a groundbreaking study on gene expression and DNA damage among patients with the rare inherited disease Friedreich's ataxia (FRDA) in the Jan. 15 issue of PLoS Genetics. Their data - the 23 gene sets associated with a genotoxic stress response and the direct biological evidence of mitochondrial and nuclear DNA damage in the blood - result in the first genetic evidence-based working model of the disease (see text box).

Leading the 11-member team was former NIEHS Senior Investigator Ben Van Houten, Ph.D., who is now at the University of Pittsburgh Cancer Institute (UPCI).

Too much of a good thing - FRDA leads to iron overload

"In FRDA, mutations in the gene frataxin reduce production of a protein that plays a role in keeping iron levels in balance within mitochondria," explained Van Houten. "Frataxin binds iron and helps build iron-sulfur clusters, which are important constituents of cellular proteins." The result is a significant reduction in mRNA and protein levels. Lead author Astrid Haugen, an NIEHS program analyst and biologist in Van Houten's NIEHS group, elaborated, "While iron is what allows blood cells to carry oxygen, too much iron is toxic to the body. Friedreich's ataxia leads to iron overload, setting the stage for cumulative DNA damage that eventually affects patients' nerve and muscle cells." 

DNA damage: the key to understanding Friedreich's ataxia 

The research team found direct evidence that FRDA patients accumulated significantly higher levels of mitochondrial and nuclear DNA damage as compared to controls. "We saw gene activity patterns that are associated with responses to DNA damage, and our comparisons and follow-up tests showed us that FRDA patients have far more damage than seen in healthy people," said Van Houten. "We found gene expression signatures that correlated with frataxin levels, age of disease onset, and a standardized measure of patient disability."

Potential breakthroughs in biomarkers, therapies

For the study, the researchers profiled gene activity in blood samples from FRDA children and adults to search for biomarkers of the disease. Patients with prolonged frataxin deficiency display DNA damage detectable in peripheral blood, which may have predictive value in future clinical trials.

The study team expects the identification of potential biomarkers to help identify therapeutic approaches for this devastating disease. These biomarkers could be useful in assessing the current status of a patient's illness, as well as the response to experimental therapies in clinical trials. Also, new drug targets might be found in the DNA repair and iron-processing pathways affected by the lack of frataxin, generating much-needed treatment breakthroughs.

(Ed Kang is a public affairs specialist in the Office of Communications and Public Liaison and a regular contributor to the Environmental Factor.)

Citation: Haugen AC, Di Prospero NA, Parker JS, Fannin RD, Chou J, Meyer JN, et al.( Exit NIEHS 2010. Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: cellular model of pathology. PLoS Genet 6(1): e1000812. doi:10.1371/journal.pgen.1000812 

Friedreich's Ataxia

Named for German physician Nikolaus Friedreich (1825-1882), who first described the condition in the 1860s, Friedreich's ataxia is a rare, inherited disease that strikes about 1 in every 50,000 people in the United States. "Ataxia" refers to coordination problems that can range from unsteadiness to complete loss of motor control. Friedreich's ataxia is the most prevalent form of inherited ataxias, and it appears equally in males and females.

Infants with Friedreich's ataxia are outwardly normal at birth. However, as they grow into childhood and early adolescence, symptoms of the disease begin to appear. The disease initially affects the nervous system, leading first to an altered walking gait and later to speech problems and muscle problems as the damage to nerve tissue in the spinal cord and to nerves that control movement in the arms and legs becomes more severe. The disease is caused by a reduction of a critical iron homeostasis protein, frataxin, found in the mitochondria.

As Friedreich's ataxia progresses in patients, they may lose the muscle control necessary to speak, read or walk. Although the rate of progression of the disease varies, many patients are forced to use a wheelchair a decade or two after symptoms appear and eventually may become completely incapacitated. The most common cause of death is heart attack due to enlarged heart (hypertrophic cardiomyopathy), usually in middle age (mean age 38 years).

There is no cure for the disease and, although some of the symptoms can be treated with medications or physical therapy, currently available treatment does little to increase lifespan or improve patients' diminishing quality of life.

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