However, in all cases, the part of the sugar chain that is critical for dystroglycan function is the part that is added by LARGE. Furthermore, work from Campbell's lab has shown that boosting LARGE activity in cells from patients with these types of muscular dystrophies is sufficient to restore dystroglycan function and overcome the defects in the cells.
By understanding what the LARGE enzyme does, the researchers have now been able to develop a test, or assay, to monitor enzyme activity.
"It's exciting that we now have this enzyme assay, which could be used in a large-scale high-throughput screen for drugs that increase (or decrease) LARGE activity," Campbell says.
Using the assay to identify compounds that boost LARGE activity might lead to potential treatments for the secondary dystroglycanopathies. The assay could also be used to look at variations in LARGE activity in patients' cells. This may help identify patients who are affected by these LARGE-related muscular dystrophies.
LARGE activity is important in other diseases
The unusual sugar chain that LARGE builds onto dystroglycan is also implicated in other diseases. A group of viruses that includes Lassa fever appear to require the sugar chain to infect cells. Lassa fever is a hemorrhagic illness that can cause serious disease and death.
Now that the researchers have determined the make-up of the unusual sugar, Campbell suggests that it will be possible to make and test it as a therapeutic to block or reduce infection by these viruses.
Campbell is also excited by another aspect of the Lassa fever link. A genome-wide study of populations in West Africa where Lassa fever is endemic suggests that the LARGE gene may be modified in this p
|Contact: Jennifer Brown|
University of Iowa Health Care