Abstract
Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed.
Highlights
Membrane transporters are basic cellular elements, which play a central role in various cellular functions and cells’ integrity
ABCC6 is one of these new players, whose deficiency is responsible for pseudoxanthoma elasticum (PXE), a rare and intriguing inherited disease with unexplained female 2 third prevalence and whose phenotype is characterized by ectopic calcifications in elastin-rich tissues such as the skin, the Burch’s membrane of the retina and the arterial wall
GGCX is required for the activation of this study found that the calcifying phenotype of Abcc6−/− mice was inhibited when sharing blood circulation with wild type animals, demonstrating the presence of an inhibitory molecule [62]
Summary
Membrane transporters are basic cellular elements, which play a central role in various cellular functions and cells’ integrity. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are a large family of 48 members involved in the pathogenesis of various inherited metabolic diseases. In this regard, ABCC6 is one of these new players, whose deficiency is responsible for pseudoxanthoma elasticum (PXE), a rare and intriguing inherited disease with unexplained female 2 third prevalence and whose phenotype is characterized by ectopic calcifications in elastin-rich tissues such as the skin, the Burch’s membrane of the retina and the arterial wall. This review will summarize the current knowledge and speculated roles of ABCC6 transporter in PXE, and in frequent acquired metabolic diseases characterized by arterial calcifications (AC)
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