Researchers at the University of Iowa noted that a genetic defect responsible for severe immune deficiency in humans might also lead to balance disorders.
The study, led by Botond Banfi, M.D., Ph.D., UI assistant professor of anatomy and cell biology, examined a specialized strain of Jackson Laboratory mice with a mutation that eradicates the production of a protein called p22phox.
When this protein is disrupted, it causes a form of chronic granulomatous disease (CGD), a severe immune deficiency, in humans. It was found that mice that do not have p22phox develop an immune deficiency that mimics human CGD. It was also found that the gene defect leads to 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. 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. 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," said Banfi.
P22phox is believed to be a critical subunit of a family of enzymes that produce reactive oxygen species (ROS). Since long, ROS were thought of as destructive molecules that can kill infecting bacteria but also damage human cells. But ROS have been recently shown to play an important role in many normal cell processes, including development and blood pressure regulation.
ROS producing family of enzymes are called NADPH oxidases (Nox), and any disruption of these enzymes has been associated with a range of diseases, including cardiovascular and neurodegenerative diseases as well as immune deficiencies like CGD.
It was found that the mice without the p22phox protein could not produce ROS in phagocytes and were predominantly vulnerable to infection. For mice without the protein, infection with bacterial pneumonia was universally fatal. On the contrary, normal mice had a 100 pct recovery rate from the same infection.
The mutant mice also found to have a severe balance disorder. It always fell off within a few seconds unlike normal mice that quickly learned how to walk on a rotating rod without falling off. Besides, it was also demonstrated that the activity of nerve cells in the inner ear that send gravity signals to the brain was missing 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. 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," said Banfi.
Even though the inner ear cells looked normal in the mutant mice, it was found that otoconia, tiny calcium carbonate crystals that are essential for sensing gravity, do not form in the inner ears of these mice. When the normal gene was restored to the mutant mice, it prevented otoconial production and barred the balance disorder.
However, although the treatment did result in improvement of the mice's immune response, the partial restoration of gene expression was not found to be 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. We may have to look for alternatives and these mice will be ideal models to test new ideas for therapy," cautioned Banfi.
The study was recently published in the Journal of Clinical Investigation.