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Gene Review

ABCC6  -  ATP-binding cassette, sub-family C...

Homo sapiens

Synonyms: ABC34, ARA, ATP-binding cassette sub-family C member 6, Anthracycline resistance-associated protein, EST349056, ...
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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


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


Associations of ABCC6 with chemical compounds


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].


  1. Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). Iliás, A., Urbán, Z., Seidl, T.L., Le Saux, O., Sinkó, E., Boyd, C.D., Sarkadi, B., Váradi, A. J. Biol. Chem. (2002) [Pubmed]
  2. Early and severe amyloidosis in a patient with concurrent familial Mediterranean fever and pseudoxanthoma elasticum. Cattan, D., Bouali, B., Chassaing, N., Martinez, F., Dupont, J.M., Dode, C., Martin, L. Br. J. Dermatol. (2006) [Pubmed]
  3. Optic disc drusen, angioid streaks, and mottled fundus in various combinations in a Sicilian family. Li Volti, S., Avitabile, T., Li Volti, G., Meloni, I., Forabosco, P., Marano, F., Bianca, S., Renieri, A. Graefes Arch. Clin. Exp. Ophthalmol. (2002) [Pubmed]
  4. Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype. Wegman, J.J., Hu, X., Tan, H., Bergen, A.A., Trip, M.D., Kastelein, J.J., Smulders, Y.M. International journal of cardiology. (2005) [Pubmed]
  5. Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. Chassaing, N., Martin, L., Calvas, P., Le Bert, M., Hovnanian, A. J. Med. Genet. (2005) [Pubmed]
  6. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Le Saux, O., Urban, Z., Tschuch, C., Csiszar, K., Bacchelli, B., Quaglino, D., Pasquali-Ronchetti, I., Pope, F.M., Richards, A., Terry, S., Bercovitch, L., de Paepe, A., Boyd, C.D. Nat. Genet. (2000) [Pubmed]
  7. Mutations in ABCC6 cause pseudoxanthoma elasticum. Bergen, A.A., Plomp, A.S., Schuurman, E.J., Terry, S., Breuning, M., Dauwerse, H., Swart, J., Kool, M., van Soest, S., Baas, F., ten Brink, J.B., de Jong, P.T. Nat. Genet. (2000) [Pubmed]
  8. Analysis of the MRP4 drug resistance profile in transfected NIH3T3 cells. Lee, K., Klein-Szanto, A.J., Kruh, G.D. J. Natl. Cancer Inst. (2000) [Pubmed]
  9. A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. Le Saux, O., Beck, K., Sachsinger, C., Silvestri, C., Treiber, C., Göring, H.H., Johnson, E.W., De Paepe, A., Pope, F.M., Pasquali-Ronchetti, I., Bercovitch, L., Marais, A.S., Viljoen, D.L., Terry, S.F., Boyd, C.D. Am. J. Hum. Genet. (2001) [Pubmed]
  10. Cytosine arabinoside kills postmitotic neurons: evidence that deoxycytidine may have a role in neuronal survival that is independent of DNA synthesis. Wallace, T.L., Johnson, E.M. J. Neurosci. (1989) [Pubmed]
  11. Successful treatment of HBs and HBeAg positive chronic liver disease: prolonged inhibition of viral replication by highly soluble adenine arabinoside 5'-monophosphate (ARA-AMP). Weller, I.V., Bassendine, M.F., Craxi, A., Fowler, M.J., Monjardino, J., Thomas, H.C., Sherlock, S. Gut (1982) [Pubmed]
  12. Evaluation of a subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonic acid oil derived from Mortierella alpina in rats. Hempenius, R.A., Lina, B.A., Haggitt, R.C. Food Chem. Toxicol. (2000) [Pubmed]
  13. Gout in females: an analysis of 92 patients. Meyers, O.L., Monteagudo, F.S. Clinical and experimental rheumatology. (1985) [Pubmed]
  14. Acute pancreatitis as the initial manifestation of systemic lupus erythematosus. Giordano, M., Gallo, M., Chianese, U., Maniera, A., Tirri, G. Zeitschrift für Rheumatologie. (1986) [Pubmed]
  15. Pseudoxanthoma elasticum: Point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11. Meloni, I., Rubegni, P., De Aloe, G., Bruttini, M., Pianigiani, E., Cusano, R., Seri, M., Mondillo, S., Federico, A., Bardelli, A.M., Andreassi, L., Fimiani, M., Renieri, A. Hum. Mutat. (2001) [Pubmed]
  16. Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Kool, M., van der Linden, M., de Haas, M., Baas, F., Borst, P. Cancer Res. (1999) [Pubmed]
  17. Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update. Hu, X., Plomp, A.S., van Soest, S., Wijnholds, J., de Jong, P.T., Bergen, A.A. Survey of ophthalmology. (2003) [Pubmed]
  18. Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistance-associated proteins in an in vitro model of the blood-brain barrier. Berezowski, V., Landry, C., Dehouck, M.P., Cecchelli, R., Fenart, L. Brain Res. (2004) [Pubmed]
  19. Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum. Hu, X., Peek, R., Plomp, A., ten Brink, J., Scheffer, G., van Soest, S., Leys, A., de Jong, P.T., Bergen, A.A. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  20. Analysis of ABCC6 (MRP6) in normal human tissues. Beck, K., Hayashi, K., Dang, K., Hayashi, M., Boyd, C.D. Histochem. Cell Biol. (2005) [Pubmed]
  21. The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line. Longhurst, T.J., O'Neill, G.M., Harvie, R.M., Davey, R.A. Br. J. Cancer (1996) [Pubmed]
  22. Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Jigorel, E., Le Vee, M., Boursier-Neyret, C., Parmentier, Y., Fardel, O. Drug Metab. Dispos. (2006) [Pubmed]
  23. Expression of the human ABCC6 gene is induced by retinoids through the retinoid X receptor. Ratajewski, M., Bartosz, G., Pulaski, L. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  24. Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Nies, A.T., Jedlitschky, G., König, J., Herold-Mende, C., Steiner, H.H., Schmitt, H.P., Keppler, D. Neuroscience (2004) [Pubmed]
  25. MOAT-E (ARA) is a full-length MRP/cMOAT subfamily transporter expressed in kidney and liver. Belinsky, M.G., Kruh, G.D. Br. J. Cancer (1999) [Pubmed]
  26. Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate. Homolya, L., Váradi, A., Sarkadi, B. Biofactors (2003) [Pubmed]
  27. Acquired Pseudoxanthoma elasticum-like syndrome in beta-thalassaemia patients. Hamlin, N., Beck, K., Bacchelli, B., Cianciulli, P., Pasquali-Ronchetti, I., Le Saux, O. Br. J. Haematol. (2003) [Pubmed]
  28. Tissue-specific expression of the ABCC6 gene. Matsuzaki, Y., Nakano, A., Jiang, Q.J., Pulkkinen, L., Uitto, J. J. Invest. Dermatol. (2005) [Pubmed]
  29. Identification of ABCC6 pseudogenes on human chromosome 16p: implications for mutation detection in pseudoxanthoma elasticum. Pulkkinen, L., Nakano, A., Ringpfeil, F., Uitto, J. Hum. Genet. (2001) [Pubmed]
  30. Heterozygous carriers of Pseudoxanthoma elasticum were not found among patients with cervical artery dissections. Morcher, M., Hausser, I., Brandt, T., Grond-Ginsbach, C. J. Neurol. (2003) [Pubmed]
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