CLINICAL CASE 27, ANSWERS and SUMMARY

Which one of the following components has a gain of function mutation to lead to atypical HUS?

CFH (23%)
CFI (0%)
MCP (19%)
C3 (34%)
THRB (23%)

Most of you said C3 mutation is a gain of function mutation followed by THRB and CFH. Again, this is a fairly new field when it comes to describing atypical HUS. There is new and emerging data all the time.  When one sees a patient and you are suspecting atypical HUS, the protein levels, you should check are: Factor H, I, B and C3, antibody for Factor H as well.  Mutation screenings are usually for Complement Factor H(CFH), Complement Factor I(CFI), Membrane co factor protein (MCP), C3, Complement Factor B(CFB) and Thrombomodulin (THRB). This is usually the workup. The complement system can be culprit. In this syndrome, due to impaired regulation of the complement system, it damages the renal endothelium.  This can occur due to loss of function mutations or gain of function mutations.  If you get a loss of function of the "regulators" such as CFI, THRB, CFH, and MCP, you get a HUS.  If you get a gain of function of the "activators" such as C3 and CFB, you get aHUS as well. So the correct answer is C3. 

Here is a nice review:-

http://www.ncbi.nlm.nih.gov/pubmed/20865638

http://www.ncbi.nlm.nih.gov/pubmed/20736981

http://www.ncbi.nlm.nih.gov/pubmed/20526633