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Immune deficiency and balance disorder result from single gene defect

GREENVILLE, N.C.   (Feb. 21, 2008)   —   A genetic defect that causes a severe immune deficiency in humans may also produce balance disorders, according to a new study by researchers at the University of Iowa, The Jackson Laboratory and East Carolina University.

The study, published online Feb. 21 in the Journal of Clinical Investigation, examined a specialized strain of Jackson Laboratory mice with a mutation that eliminates the production of a protein called p22phox. Disruption of this protein causes a form of chronic granulomatous disease (CGD) - a severe immune deficiency - in humans.

The researchers found that mice without p22phox develop an immune deficiency that mimics human CGD. They also discovered that the gene defect produces a severe balance disorder in the mice caused by loss of gravity-sensing crystals in the inner ear.

"The implication is that human patients with CGD caused by defects in this gene may also have balance disorders," said Botond Banfi, M.D., Ph.D., University of Iowa assistant professor of anatomy and cell biology and senior author of the study. "If that is the case, this would be the first patient population where we could study the consequences of losing the sensation of gravity.

"We hope that clinicians will test the balance capacity of those patients with this rare form of CGD," Banfi added. "Although it is hard to say what the consequences might be of not sensing gravity, these patients may be more prone to accidents like falling."

In addition to Banfi, the research team included Yoko Nakano, Ph.D., a UI postdoctoral fellow in Banfi's laboratory and lead author of the study; David Bergstrom, Ph.D., research scientist, and Chantal Longo-Guess, B.S., research assistant in the Genetic Resource Science group at The Jackson Laboratory; William Nauseef, M.D., UI professor of internal medicine; and Sherri Jones, Ph.D., associate professor of communication sciences and disorders in ECU's College of Allied Health Sciences.

In the study, Jones, an audiologist and expert in vestibular disorders, measured inner ear function of the mice, specifically the function of the balance sensing organs which are one component of the inner ear vestibular system.

"My lab has developed techniques to measure the gravity sensing organs non-invasively, and we are using this technique as well as other approaches in order to understand the functional role for many genes that are critical for normal inner ear development and vestibular function," Jones said.

P22phox is emerging as a critical subunit of a family of enzymes that produce reactive oxygen species (ROS). For many years, ROS were simply thought of as destructive molecules that can kill infecting bacteria but also damage human cells. More recently, however, ROS have been shown to play an important role in many normal cell processes, including development and blood pressure regulation. The family of enzymes that produce ROS are called NADPH oxidases (Nox), and disruption of these enzymes has been implicated in a range of diseases, including cardiovascular and neurodegenerative diseases as well as immune deficiencies like CGD.

There are several forms of CGD caused by different genetic defects affecting the Nox complex of pathogen-fighting cells called phagocytes. CGD caused by lack of p22phox is one of the least common forms of the disease in humans. The mutant mouse, which was produced by The Jackson Laboratory's Neuromutagenesis Facility, represents the first animal model for this version of CGD and will be helpful in understanding the disease and developing potential treatments.

The study found that the mice without the p22phox protein were unable to produce ROS in phagocytes and were particularly susceptible to infection. For mice without the protein, infection with bacterial pneumonia was universally fatal. In contrast, normal mice had a 100 percent recovery rate from the same infection.
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