Disease relevance of ABCC6

• Mutations in the ABCC6 (MRP6) gene cause pseudoxanthoma elasticum (PXE), a rare heritable disorder resulting in the calcification of elastic fibers [1].
• ABCC6 deficiency may have increased the severity of amyloidosis by increasing the deposition in target tissues of heparan sulphate, which colocalizes spatially and temporally with amyloid proteins, and/or by decreasing the therapeutic activity of colchicine [2].
• CONCLUSIONS: The dominant transmission of optic disc drusen, mottled fundus, and angioid streaks in this family is not due to alterations in the ABCC6 gene [3].
• CONCLUSIONS: Carriers for the ABCC6 R1141X mutation, which is frequent and confers a high risk of premature coronary artery disease, do not commonly have skin or eye abnormalities consistent with a mild PXE phenotype [4].
• The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres [5].

High impact information on ABCC6

• Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (ABCC6) [6].
• Mutations in ABCC6 cause pseudoxanthoma elasticum [7].
• In addition to these two transporters, there are at least four other human MRP subfamily members (MRP3 through MRP6) [8].
• We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6 [9].
• The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2) [9].

Chemical compound and disease context of ABCC6

• Cytidine could block ARA C toxicity, but it was 40 times less potent than 2'-deoxycytidine [10].
• Successful treatment of HBs and HBeAg positive chronic liver disease: prolonged inhibition of viral replication by highly soluble adenine arabinoside 5'-monophosphate (ARA-AMP) [11].
• Pup weight gain in the ARA/DHA-oil group was lower than the controls administered equal amounts of corn oil [12].
• Forty patients were diagnosed by finding tophi or urate crystals in the synovial fluid, 16 patients had the ARA clinical criteria for gout, and a further 36 patients were considered to have good clinical grounds for gouty arthritis [13].
• A 20-year-old female with three laboratory ARA criteria pro SLE (LE cells, FANA, and positive Coombs test with hemolytic anemia), not under steroid therapy, developed polyarthritis, erythematous rash and acute pancreatitis simultaneously [14].

Biological context of ABCC6

• In the three ABCC6 mutant forms examined, the loss of transport activity suggests that these mutations result in a PXE phenotype through a direct influence on the transport activity of this ABC transporter [1].
• In isolated membranes ATP binding as well as ATP-dependent active transport by ABCC6 was demonstrated [1].
• In the present study a cDNA encoding a full-length normal variant of ABCC6 was amplified from a human kidney cDNA library, and the protein was expressed in Sf9 insect cells [1].
• Mutation analysis on the other allele of the family, as well as on two additional sporadic cases, revealed nonsense (Y227X, R518X, R1164X) and frame-shift (c.960delC) mutations in ABCC6 (MRP6) further confirming the role of this multi-drug resistance gene in the etiology of pseudoxanthoma elasticum [15].
• The MRP6 gene is located on chromosome 16, immediately next to MRP1, and encodes a protein of 1503 amino acids with a predicted molecular weight of Mr 165,000 [16].

Anatomical context of ABCC6

• Similar molecules transported by ABCC6 in humans may be essential for extracellular matrix deposition or turnover of connective tissue at specific sites in the body [17].
• DNA blot (Southern) analysis showed that MRP6 or a part of it is also amplified in these cell lines [16].
• Moreover, MRP6 was the only transporter whose endothelial mRNA expression was influenced by the presence of pericytes [18].
• Immunocytochemical staining of cultured dermal fibroblasts with ABCC6-specific monoclonal antibodies showed no evidence of the presence of a truncated protein in patients with PXE who were homozygous for R1141X [19].
• In addition, ABCC6 mRNA and protein were present in most neurons of the brain, in alveolar macrophages in the lungs and lymphocytes in the lymph node [20].

Associations of ABCC6 with chemical compounds

• We found that glutathione conjugates, including leukotriene C(4) and N-ethylmaleimide S-glutathione (NEM-GS), were actively transported by human ABCC6 [1].
• The 3' end of the MRP6 protein was found to be almost identical with the anthracycline resistance associated (ARA) protein identified previously in epirubicin-selected leukemia cells [16].
• The primary amino acid sequence of ARA indicates that it is 49.5 kDa without glycosylation, and that it has one potential glycosylation site [21].
• PB also decreased MRP6 expression, whereas mRNA levels of OCT1 and OATP8 were down-regulated by RIF and OPZ, respectively [22].
• Expression of the human ABCC6 gene is induced by retinoids through the retinoid X receptor [23].

Other interactions of ABCC6

• To assess a possible role for MRP6 in multidrug resistance, we examined a large panel of resistant cell lines for the (over)expression of MRP6 [16].
• To identify MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs, we analyzed the expression and localization of MRP1-MRP6 in rapidly frozen perilesional samples of several regions of adult human brain obtained during neurosurgery [24].
• Isolation of MOAT-E helps to define the MRP/cMOAT subfamily of transporters [25].
• The human MRP4, MRP5 and MRP6 have only partially been characterized [26].
• The inherited PXE is caused by mutations in the ATP-binding cassette, subfamily C (CFTR/MRP), member 6 (ABCC6) gene and is characterized by mineralized elastic fibres in dermal, vascular and ocular tissues [27].

Analytical, diagnostic and therapeutic context of ABCC6

• Subcloning and sequencing of these PCR products indicated that they reflected aberrant splicing in the 3' end of the ABCC6 mRNA, resulting in each case in a premature termination codon [28].
• To explore the tissue-specific expression of ABCC6, we first examined various mouse tissues by RT-PCR [28].
• ABCC6 expression was analyzed by RT-PCR and immunocytochemistry with ABCC6-specific monoclonal antibodies [19].
• Sequence analysis of ABCC6-psi 1 revealed it to be a truncated copy of ABCC6, which contains the upstream region and exon 1 through intron 9 of the gene [29].
• In this study of patients with spontaneous cervical artery dissections (sCAD) we searched for mutations in ABCC6, the candidate gene for Pseudoxanthoma elasticum (PXE).Genomic DNA samples from 12 sCAD patients with pronounced electron microscopic alterations in their dermal connective tissue and from 2 patients with PXE were analysed [30].

References