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Study Shows Gene Defect Plays Role in Balance Disorder

A genetic defect that causes a severe immune deficiency in humans may also produce balance disorders, according to a new study by researchers at East Carolina University, the University of Iowa, and The Jackson Laboratory.

The study, published online Feb. 21 in the “Journal of Clinical Investigation,” examined a specialized strain of 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, 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.

In addition to Banfi, the research team included Yoko Nakano, a postdoctoral fellow in Banfi’s laboratory; David Bergstrom, research scientist, and Chantal Longo-Guess, research assistant in the Genetic Resource Science group at The Jackson Laboratory; William Nauseef, professor of internal medicine; and Sherri Jones, 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 to understand the functional role for many genes that are critical for normal inner ear development and vestibular function,” Jones said.  

The study found that the mice without the p22phox protein 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.

The mutant mice also had a severe balance disorder. Unlike normal mice that quickly learned how to walk on a rotating rod without falling off, the mutant mice always fell off within a few seconds. Additionally, the study showed that activity of nerve cells in the inner ear responsible for sending gravity signals to the brain was absent in the mutant mice.

“Loss of p22phox affects two enzyme complexes: one in phagocytes that is responsible for the immune defect, and one in the inner ear,” Banfi said.

“Since this is the first mouse model for defects in the p22phox subunit, this is the first time that its role in balance has been revealed.”

“In this particular study, Dr. Bergstrom had shown that the gravity sensing organs were not functioning in the mutant mice and my lab demonstrated that the gravity sensing organs were functioning normally in the mice where the genetic problem had been repaired,” Jones said.  “To my knowledge, this is the first study to show repaired vestibular neural function as a result of genetic engineering.”

Although inner ear cells looked normal in the mutant mice, the researchers discovered that otoconia - tiny calcium carbonate crystals that are essential for sensing gravity - do not form in the inner ears of these mice.

Restoring the normal gene to the mutant mice rescued otoconial production and prevented the balance disorder.

However, although the treatment did improve the mice’s immune response, the partial restoration of gene expression was not sufficient to cure the immune deficiency completely.

“This may mean that gene therapy, which would only partially restore expression of p22phox, would not completely cure CGD in humans,” cautioned Banfi. “We may have to look for alternatives and these mice will be ideal models to test new ideas for therapy.”

The study was funded in part by grants from the National Institutes of Health.


This page originally appeared in the Feb. 29, 2008 issue of Pieces of Eight. Complete issue is archived at