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.

中文翻译：

---

与多发性骨髓瘤、二尖瓣主动脉瓣和 Von Hippel-Lindau 综合征相关的金属蛋白酶的功能获得

一名被诊断患有多发性骨髓瘤、二尖瓣主动脉瓣和 Von Hippel-Lindau 综合征的患者接受了全外显子组测序，以寻找这三种病理的统一遗传原因。该患者在基质金属蛋白酶 9 (MMP-9) 的 N 端区域（前结构域）具有精氨酸单点突变为半胱氨酸 (R24C)。前结构域与该酶的催化位点相互作用，使其失活。MMP-9 先前已与患者遭受的所有三种病症相关联。我们假设在前域中观察到的突变会影响这种酶的活性。我们表达了 MMP-9 的重组版本，并且对其生化特性的研究表明 MMP-9 R24C 是一种组成型活性酶原。据我们所知，