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 published in the Journal of Clinical Investigation.  The team studied the effect of elimination of the p22phox gene in mice models.  Disruption of this protein causes a form of chronic granulomatous disease (CGD) — a severe immune deficiency — in humans.  The study showed that mice without p22phox develop an immune deficiency that mimics human CGD.   In addition, 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.  Unlike normal mice that quickly learned how to walk on a rotating rod without falling off, the mutant mice indefinately fell off within a few seconds.   Furthermore, 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. 

P22phox is emerging as a critical subunit of a family of enzymes that produce reactive oxygen species (ROS).   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 a key role in many normal cell processes, including development and blood pressure regulation. The group of enzymes that produce ROS are called NADPH oxidases (Nox).   Disruption of these enzymes has been implicated in a range of diseases, including cardiovascular and neurodegenerative diseases as well as immune deficiencies like CGD.

In this study, 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.   It is speculated that the superoxide radicals under the right pH and calcium concentrations promote such crystal formation.  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.