One of the genes responsible for CGD may affect a person’s balance. This surprising discovery has come from researchers at universities and laboratories in Iowa and North Carolina, USA. The researchers have found that mice lacking the gene p22phox not only develop CGD that mimics the human condition but also show signs of a severe balance disorder.
CGD caused by lack of p22phox is one of the least common forms of the disorder in humans. It can affect about 1 in 20 people with CGD. The results published in the Journal of Clinical Investigation show that the balance problems in the mutant mice were due to the lack of formation of gravity-sensing crystals in the inner ear.
Dr Botond Banfi, assistant professor of anatomy and cell biology and member of the Inflammation Program at the University of Iowa and senior author on the paper comments ‘The implication is that human patients with CGD caused by defects in this gene may also have balance disorders that are under recognised. If that is the case, this would be the first patient population where we could study the consequences of losing the ability to sense gravity.’
‘We hope that this will alert clinicians to test the balance capacity of those patients with this rare form of CGD’, added Dr Banfi. ‘Although it is hard to say what the consequences might be of not sensing gravity, these patients may be prone to accidents like falling. We have no evidence as yet whether this is the case or not and it needs more investigation.’
Unlike normal mice that quickly learned to walk on a rotating rod without falling off, the mice lacking the p22phox always fell off after a few seconds. The study showed that the inner ear defect was specific to the gravity-sensing organs, whereas the hearing function of the ear was intact in the mutant mice.
The study is important in a number of respects. It is the first time that a mouse model of the p22phox CGD deficiency has been developed and this will be extremely helpful in understanding this form of CGD and developing potential treatments. Secondly, a new function of the p22phox gene has been discovered. ‘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,’ Dr Banfi said.
‘P22phox is one of the subunits affected in CGD and that makes up the enzyme NADPH oxidase. This family of enzymes produces reactive oxygen species (ROS). In the past we have always thought of them as molecules that are able to kill bacteria in normal neutrophils but are absent in patients with CGD. Now we know that ROS have many more roles in the body such as in development and blood pressure regulation’, said Professor William Nauseef, a co-author on the paper and a previous grant holder from the CGD Research Trust. ‘This study has highlighted that ROS are important in the formation of the tiny calcium carbonate crystals that are essential for sensing gravity in the inner ear,’ added Professor Nauseef.
One other critical finding has implications for the future therapy of p22phox CGD deficiency. When normal gene function was restored in the mice the balance disorder was resolved. However, although the treatment did improve the mice’s ability to fight infections, 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’, commented Dr Banfi. ‘We may have to look for alternatives and these mice will be ideal models to test new ideas for therapy.’
Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice. Yoko Nakano, Chantal M. Longo-Guess, David E. Bergstrom, William M. Nauseef, Sherri M. Jones and Botond Bánfi. J. Clin. Invest. March 2008.
http://content.the-jci.org/articles/view/33835/pdf
IMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
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