Gain of function of a metalloproteinase associated with multiple myeloma, bicuspid aortic valve, and Von Hippel-Lindau syndrome.

A patient diagnosed with multiple myeloma, bicuspid aortic valve, and Von Hippel-Lindau syndrome underwent whole-exome sequencing seeking a unified genetic cause for these three pathologies. The patient possessed a single-point mutation of arginine to cysteine (R24C) in the N-terminal region(pro-domain) of matrix metalloproteinase 9 (MMP-9). The pro-domain interacts with the catalytic site of this enzyme rendering it inactive. MMP-9 has previously been associated with all three pathologies suffered by the patient. We hypothesized that the observed mutation in the pro-domain would influence the activity of this enzyme. We expressed recombinant versions of MMP-9 and an investigation of their biochemical properties revealed that MMP-9 R24C is a constitutively active zymogen. To our knowledge, this is the first example of a mutation that discloses catalytic activity in the pro-form in any of the 24 human MMPs.