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.
Gain of function of a metalloproteinase associated with multiple myeloma, bicuspid aortic valve, and Von Hippel–Lindau syndrome
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Scott J. Snipas, Roberto Jappelli, Ali Torkamani, Giovanni Paternostro, Guy S. Salvesen; Gain of function of a metalloproteinase associated with multiple myeloma, bicuspid aortic valve, and Von Hippel–Lindau syndrome. Biochem J 29 July 2022; 479 (14): 1533–1542. doi: https://doi.org/10.1042/BCJ20220166
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