Although it is known that mutations in the CFTR gene cause the disease, variations in other genes between individuals with CF modify the severity of the disease. For example, the gene responsible for making the MBL2 protein has been suggested to modify lung function in individuals with CF; however, its precise roles in the disease have not been well understood. In a new study, Julian Zielenski and his colleagues at the Hospital for Sick Children, Toronto, found that genetic variations that modify MBL2 expression were associated with more severe clinical symptoms of CF.

The researchers compared levels of MBL2 in the blood of more than 1,000 CF patients and found that patients deficient in MBL2 were often younger when first infected with the bacteria Pseudomonas aeruginosa, and that their lung function declined more rapidly than patients with normal or high levels of the protein. These associations between MBL2 and CF severity were even more pronounced in patients that overproduced the protein TGF-beta-1. The authors argue that these findings might provide a basis for new approaches for treating those individuals with CF who are at risk of such increased disease severity. In an accompanying commentary, Frank Accurso and Marci Sontag at the University of Colorado Denver further suggest that it might be useful to screen for gene variants that cause the production of high levels of MBL2 and TGF-beta-1, as well as other genes that modify the course of CF, in newborn CF screening.

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"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."

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 team was also able to track the location of the Nox complex during embryonic development of the inner ear by visualizing the location of p22phox. Interestingly, the complex does not reside in the same place that the otoconia form leading the researchers to propose a new mechanism by which the Nox complex controls production of the crystals.

"We speculate that superoxide radicals generated by the p22phox “containing complex facilitate the formation of otoconia by producing the right conditions, high pH and high calcium concentration, in the compartment where these calcium carbonate crystals form," Banfi explained.

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

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