Project 451911

Patients with a severe infection caused by a bacteria called pneumococcus can injure their kidneys, leading to protein in the urine and blood clots in the kidneys. The injury is caused by an enzyme called neuraminidase A (or NanA for short) that is released in the blood by the bacteria. An enzyme is a molecular machine that does one specific function very well. In this case, NanA removes a particular sugar called sialic acid from proteins on kidney cells. Why is this a problem? On cells, many proteins have essential functions that require the presence of sialic acid on them. For example, they can work like docking stations for circulating blood cells. Sialic acid also helps prevent cells from sticking to each other in the blood because of its negative charge (like trying to bring two magnets together). The big problem: we don't know why having less sialic acid on proteins causes clotting in the kidneys. We recently discovered a new genetic disease in patients who have blood clots in their kidneys but no pneumococcus infection. They all have mutations in the gene ST3GAL1, an enzyme that adds sialic acid sugars when cells build proteins. The cells then ship the proteins to where they are supposed to work. We showed in the lab that mutant ST3GAL1 cannot work as usual. As a result, the patients' cells are making proteins that do not have sialic acid sugars on them. What's interesting is that ST3GAL1 adds the same sialic acid that is removed by NanA. Because of that, we propose to study the two diseases to figure out what is the common thread between them. Our experiments will help show why abnormal sialic acid biology causes so many problems in kidneys. We think that there are specific proteins that require sialic acid to play an essential role in preventing blood clots in the kidney blood vessels. A better understanding of these diseases is needed to develop new treatments for these patients.