From membrane to mineralization: the curious case of the ABCC6 transporter

Abstract

ATP‐binding cassette subfamily C member 6 gene/protein (ABCC6) is an ATP‐dependent transmembrane transporter predominantly expressed in the liver and the kidney. ABCC6 first came to attention in human medicine when it was discovered in 2000 that mutations in its encoding gene, ABCC6, caused the autosomal recessive multisystemic mineralization disease pseudoxanthoma elasticum (PXE). Since then, the physiological and pathological roles of ABCC6 have been the subject of intense research. In the last 20 years, significant findings have clarified ABCC6 structure as well as its physiological role in mineralization homeostasis in humans and animal models. Yet, several facets of ABCC6 biology remain currently incompletely understood, ranging from the precise nature of its substrate(s) to the increasingly complex molecular genetics. Nonetheless, advances in our understanding of pathophysiological mechanisms causing mineralization lead to several treatment options being suggested or already tested in pilot clinical trials for ABCC6 deficiency. This review highlights current knowledge of ABCC6 and the challenges ahead, particularly the attempts to translate basic science into clinical practice.

The incredible diversity of structures and functions of ABC transporters

“…If integration of molecular details into a physiological context is indeed possible, our grasp on the structure and function of ABCs should lead to clinically relevant insights. Evolving biochemical and structural models might help develop therapies to better address diseases related to the malfunctioning of ABCs such as CFTR or ABCC6, resulting in cystic fibrosis and PXE (Pseudoxanthoma elasticum), respectively [22–25].…”

Minocycline Counteracts Ectopic Calcification in a Murine Model of Pseudoxanthoma Elasticum: A Proof-of-Concept Study

“…Pseudoxanthoma elasticum (PXE; OMIM #264800) is considered a paradigm of hereditary ectopic calcification disorders and is typically caused by bi-allelic pathogenic variants in the ABCC6 gene [8]. ABCC6 encodes a transmembrane ATP-dependent efflux transporter primarily expressed on the basolateral membrane of hepatocytes and, to a lesser extent, in renal proximal tubular cells, transferring a still-unknown substrate [9,10]. Clinically, PXE patients develop extensive mineralization of elastic fibers from late childhood onwards, affecting the mid dermis of the skin (resulting in yellowish papular lesions and excessive skin folds), the retinal Bruch membrane (complicated by choroidal neovascularization, hemorrhage and vision loss) and the medial layer of arteries (predisposing to stroke and peripheral artery disease) [11].…”

The Expression Level of ABCC6 Transporter in Colon Cancer Cells Correlates with the Activation of Different Intracellular Signaling Pathways

“…The ATP-binding cassette sub-family C member 6 transporter (ABCC6) is an ATP-dependent transporter mainly found in the basolateral plasma membrane of the liver and kidney. Mutations in the ABCC6 gene are associated with pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by a progressive ectopic calcification of elastic fibers in dermal, ocular, and vascular tissues [ 1 , 2 , 3 , 4 ]. Although the structural features of the protein have been quite characterized [ 5 , 6 , 7 , 8 , 9 ], a lot of evidence suggests that, apart from directly supplying the extracellular matrix with PPi, ABCC6 may be involved in other specific functions, such as cholesterol homeostasis [ 10 , 11 ].…”