3.A.1.208.10
Multidrug (anthracycline) resistance organic anion efflux pump (ABCC6; ABC-C6; MRP6; MOAT-E) - the ectopic mineralization disorder, pseudoxanthoma elasticum disease (PXE), protein (Vanakker et al. 2013; Rasmussen et al. 2013). It exports glutathione metal conjugates as well as leukotriene C₄, DNP, and N-ethylmaleimide S-glutathione, and also exports anthracyclines, epipodophyllotoxins, cisplatin, and probably probenecid, benzbromarone and indomethacin (Chen and Tiwari, 2011).  The system participates in networds of complex diseases (De Vilder et al. 2015). This transporter has an extra N-terminal domain (TMD0) and a loop, L0.  TMD0 is not required for transport function, but L0 maintains ABCC6 in a targeting-competent state for the basolateral membranes of liver and kidney cells and might be involved in regulating the NBDs (Miglionico et al. 2016). PXE is a disease of altered elastic properties in multiple tissues. Many of these mutations influence various steps in the biosynthetic pathway, minimally altering local domain structure but adversely impacting ABCC6 assembly and trafficking (Ran and Thibodeau 2016). PXE is an ectopic, metabolic mineralization disorder that affects the skin, eye, and vessels. ABCC6 is assumed to mediate efflux of one or several small molecule compounds from the liver cytosol to the circulation. In mice, abrogating ABCC6 function causes alterations in the liver metabolic profile, suggesting that PXE is a metabolic disease originating from a liver disturbance (Rasmussen et al. 2016). Thus, MRP6 is involved in the regulation of tissue calcification in mammals, and mutations are associated with human ectopic calcification disorders. Comparative analyses of ABCC6 and ABCC1 from invertebrates to vertebrates revealed a bony endoskeleton first evolved with ABCC1, while the ABCC6 gene is only found in bony vertebrate genomes (Parreira et al. 2018). Pseudoxanthoma elasticum (PXE), a heritable multi-system ectopic mineralization disorder, is caused by inactivating mutations in the ABCC6 gene. The encoded protein has a specialized efflux function in hepatocytes by contributing to plasma levels of PPi, a potent inhibitor of mineralization in soft connective tissues. Reduced plasma PPi levels underlie the ectopic mineralization in PXE (Kowal et al. 2021).  AbcC6 deficiency prevents rhabdomyolysis-induced acute kidney injury (Casemayou et al. 2023).  Most cases of Pseudoxanthoma elasticum (PXE) are caused by inactivating pathogenic variants in the ABCC6 gene encoding a hepatic transmembrane efflux transporter, which facilitates the extracellular release of ATP, the precursor of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification (Li et al. 2024).