The ABCC6 transporter: what lessons can be learnt from other ATP-binding cassette transporters?

Abstract

ABC transporters represent a large family of ATP-driven transmembrane transporters involved in uni- or bidirectional transfer of a large variety of substrates. Divided in seven families, they represent 48 transporter proteins, several of which have been associated with human disease. Among the latter is ABCC6, a unidirectional exporter protein primarily expressed in liver and kidney. ABCC6 deficiency has been shown to cause the ectopic mineralization disorder pseudoxanthoma elasticum (PXE), characterized by calcification and fragmentation of elastic fibers, resulting in oculocutaneous and cardiovascular symptoms. Unique in the group of connective tissue disorders, the pathophysiological relation between the ABCC6 transporter and ectopic mineralization in PXE remains enigmatic, not in the least because of lack of knowledge on the substrate(s) of ABCC6 and its unusual expression pattern. Because many features, including structure and transport mechanism, are shared by many ABC transporters, it is worthwhile to evaluate if and to what extent the knowledge on the physiology and pathophysiology of these other transporters may provide useful clues toward understanding the (patho)physiological role of ABCC6 and how its deficiency may be dealt with.

Dietary Pyrophosphate Modulates Calcification in a Mouse Model of Pseudoxanthoma Elasticum: Implication for Treatment of Patients

“…Indeed, in addition to producing considerable inter-and intra-familial phenotypical variability (Uitto et al, 2014), identical mutations can also lead, in humans, to the relatively mild PXE phenotype or severe generalized arterial calcification of infancy (Nitschke et al, 2012) and mice (Le Corre et al, 2012). The presence of modifier genes modulating calcification in PXE has been investigated, but results are thus far inconclusive (Hendig et al, 2013;Hosen et al, 2015;Vanakker et al, 2013). Given the significant influence of elevated PPi in the institutional diet fed to our Abcc6 e/e mice, the widespread presence of PPi in processed food, and its efficient oral absorption in humans (our data; Dedinszki et al, 2017), we suggest that dietary preference is a plausible explanation for the heterogeneous manifestations of PXE.…”

ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

“…In contrast to other human transmembrane transporters, the characteristics and substrate spectra of which have already been explored, the function and physiological role of ABCC6 is still unclear [ 4 ]. Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder with an estimated prevalence of 1: 25.000- 50.000 [ 5 ].…”

ABCC6 plays a significant role in the transport of nilotinib and dasatinib, and contributes to TKI resistance in vitro, in both cell lines and primary patient mononuclear cells

“…ABCC6 (MRP6) belongs to the Multidrug Resistance Protein (MRP) superfamily and is capable of extruding a wide variety of substrates from cells[ 11 ]. ABCC6 bears striking sequence homology to ABCC1 and is thought to have arisen from a gene duplication[ 12 – 14 ]. While a biological substrate has not yet been elucidated, ABCC6 is known to transport lipophilic molecules of negative charge[ 15 , 16 ] and is primarily expressed at points of drug extrusion such as the liver and the kidney[ 12 , 17 , 18 ].…”