ABCC6, encoding the trans-membrane protein ABCC6/MRP6, belongs to the adenosine triphosphate-binding cassette (ABC) gene subfamily C. It is primarily and highly expressed in the liver and kidney. Although its precise physiological function and natural substrate(s) are unknown, it may be involved in active transport of intracellular compounds to the extracellular environment. It facilitates the cellular efflux of ATP, which is related to the inorganic pyrophosphate (PPi)-mediated calcification inhibition pathway, playing an important role in mineralization homeostasis [1,2,4,5]. Animal models like mice, rat, and zebrafish have been crucial for studying ABCC6 [1].

ABCC6 dysfunction is the primary cause of pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, and also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders. In mice lacking Abcc6 and Ldlr genes fed an atherogenic diet, ABCC6 deficiency causes changes in lipoproteins, decreases HDL cholesterol, and induces atherosclerosis, showing a novel role of ABCC6 in influencing plasma lipoproteins and atherosclerosis [1,3].

In conclusion, ABCC6 is essential in mineralization homeostasis and is associated with ectopic calcification-related diseases such as PXE and GACI. Mouse models, especially those with Abcc6 deficiency, have been valuable in revealing its role in ectopic calcification and atherosclerosis, helping us understand the underlying mechanisms and potentially guiding future therapeutic strategies for these diseases.

References:

1. Shimada, Briana K, Pomozi, Viola, Zoll, Janna, Martin, Ludovic, Le Saux, Olivier. 2021. ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions. In International journal of molecular sciences, 22, . doi:10.3390/ijms22094555. https://pubmed.ncbi.nlm.nih.gov/33925341/

2. Bergen, Arthur A B, Plomp, Astrid S, Hu, Xiaofeng, de Jong, Paulus T V M, Gorgels, Theo G M F. 2006. ABCC6 and pseudoxanthoma elasticum. In Pflugers Archiv : European journal of physiology, 453, 685-91. doi:. https://pubmed.ncbi.nlm.nih.gov/16604369/

3. Brampton, Christopher, Pomozi, Viola, Chen, Li-Hsieh, Martin, Ludovic, Le Saux, Olivier. 2021. ABCC6 deficiency promotes dyslipidemia and atherosclerosis. In Scientific reports, 11, 3881. doi:10.1038/s41598-021-82966-y. https://pubmed.ncbi.nlm.nih.gov/33594095/

4. Váradi, András, Szabó, Zalán, Pomozi, Viola, Fülöp, Krisztina, Arányi, Tamás. . ABCC6 as a target in pseudoxanthoma elasticum. In Current drug targets, 12, 671-82. doi:. https://pubmed.ncbi.nlm.nih.gov/21039331/

5. Verschuere, Shana, Van Gils, Matthias, Nollet, Lukas, Vanakker, Olivier M. 2020. From membrane to mineralization: the curious case of the ABCC6 transporter. In FEBS letters, 594, 4109-4133. doi:10.1002/1873-3468.13981. https://pubmed.ncbi.nlm.nih.gov/33131056/