Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Abstract

Mutations in the ABCC6 gene, encoding the multidrug resistance-associated protein 6 (MRP6), cause pseudoxanthoma elasticum (PXE). This heritable disorder leads to pathological alterations in connective tissues. The implication of MRP6 deficiency in PXE is still unknown. Moreover, nothing is known about a possible compensatory expression of other ATP binding-cassette (ABC) transporter proteins in MRP6-deficient cells. We investigated the gene expression profile of 47 ABC transporters in human dermal fibroblasts of healthy controls (n ¼ 2) and PXE patients (n ¼ 4) by TaqMan low-density array. The analysis revealed the expression of 37 ABC transporter genes in dermal fibroblasts. ABCC6 gene expression was not quantifiable in fibroblasts derived from PXE patients. Seven genes (ABCA6, ABCA9, ABCA10, ABCB5, ABCC2, ABCC9 and ABCD2) were induced, whereas the gene expression of one gene (ABCA3) was decreased, comparing controls and PXE patients (with at least twofold changes). We reanalyzed the gene expression of selected ABC transporters in a larger set of dermal fibroblasts from controls and PXE patients (n ¼ 6, each). Reanalysis showed high interindividual variability between samples, but confirmed the results obtained in the array analysis. The gene expression of ABC transporter genes, as well as lineage markers of PXE, was further examined after inhibition of ABCC6 gene expression by using specific small-interfering RNA. These experiments corroborated the observed gene expression alterations, most notably in the ABCA subclass (up to fourfold, Po0.05). We therefore conclude that MRP6-deficient dermal fibroblasts exhibit a distinct gene expression profile of ABCA transporters, potentially to compensate for MRP6 deficiency. Moreover, our results point to a function for ABCC6/MRP6 in sterol transport, as sterols are preferential regulators of ABCA transporter activity and expression. Further studies are now required to uncover the role of ABCA transporters in PXE.

A Mouse Model of β-Thalassemia Shows a Liver-Specific Down-Regulation of Abcc6 Expression

“…Therefore, it is possible that Abcc2 also responded to the same NF-E2-related molecular signal(s) as Abcc6. The down-regulation is also worth noting because of the results recently published by Hendig and colleagues, 46 which showed changes in ATP-binding cassette transporter gene expression in response to ABCC6 knockdown (siRNA) or knockout (PXE fibroblasts). In this report, the human ABCC2 is up-regulated in response to ABCC6 down-regulation or absence.…”

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

“…Primary human dermal fibroblasts from four PXE patients were isolated and specified as described previously [18]. None of the investigated patients was reported to suffer from dyslipidemia.…”

“…Moreover, Beck et al detected ABCC6 mRNA in murine intestine, colon, brain, and eye [17]. Human dermal fibroblasts served as an appropriate model for soft tissue calcification in recent studies [7,18,19]. In addition to human skin fibroblasts, Abcc6-deficient (Abcc6 − / − ) mouse models were established for the examination of PXE pathogenesis [20,21].…”

Expression of the 49 human ATP binding cassette (ABC) genes in pluripotent embryonic stem cells and in early- and late-stage multipotent mesenchymal stem cells

“…They only appear during endoderm and ectoderm development. [53][54][55] They transport steroids (ABCC11) or sterols (ABCG5 and ABCG8), or have MDR (ABCB5) or unknown activities (ABCC12) ( Table 1).…”