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ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis

Nature Genetics volume 44, pages 170–173 (2012)Cite this article

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Abstract

The human ATP-binding cassette (ABC) transporter ABCB6 has been described as a mitochondrial porphyrin transporter essential for heme biosynthesis1, but it is also suspected to contribute to anticancer drug resistance2,3,4, as do other ABC transporters located at the plasma membrane. We identified ABCB6 as the genetic basis of the Lan blood group antigen expressed on red blood cells but also at the plasma membrane of hepatocellular carcinoma (HCC) cells, and we established that ABCB6 encodes a new blood group system (Langereis, Lan). Targeted sequencing of ABCB6 in 12 unrelated individuals of the Lan(−) blood type identified 10 different ABCB6 null mutations. This is the first report of deficient alleles of this human ABC transporter gene. Of note, Lan(−) (ABCB6−/−) individuals do not suffer any clinical consequences, although their deficiency in ABCB6 may place them at risk when determining drug dosage.

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Figure 1: Characterization of the Lan blood group antigen expression on RBCs with the OSK43 monoclonal antibody.
Figure 2: Identification of ABCB6 as the gene encoding the Lan blood group antigen.
Figure 3: Expression of the Lan antigen on human cancer cell lines.

References

  1. Krishnamurthy, P.C. et al. Identification of a mammalian mitochondrial porphyrin transporter. Nature 443, 586–589 (2006).

    Article  CAS  Google Scholar 

  2. Szakács, G. et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 6, 129–137 (2004).

    Article  Google Scholar 

  3. Kelter, G. et al. Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS ONE 2, e798 (2007).

    Article  Google Scholar 

  4. Yasui, K. et al. Alteration in copy numbers of genes as a mechanism for acquired drug resistance. Cancer Res. 64, 1403–1410 (2004).

    Article  CAS  Google Scholar 

  5. Cartron, J.-P. Blood group antigens structure and function: recent advances. in Hematology Education: the Education Program for the Annual Congress of the European Hematology Association Vol. 2, 158–174 (2008).

    Google Scholar 

  6. Daniels, G. The molecular genetics of blood group polymorphism. Hum. Genet. 126, 729–742 (2009).

    Article  CAS  Google Scholar 

  7. van der Hart, M., Moes, M., van der Veer, M. & van Loghem, J.J. Ho and Lan—two new blood group antigens. in Proceedings of the 8th Congress of the European Society of Haematology 493 (Vienna, 1962).

  8. Smith, D.S. et al. Haemolytic disease of the newborn caused by anti-Lan antibody. BMJ 3, 90–92 (1969).

    Article  CAS  Google Scholar 

  9. Page, P.L. Hemolytic disease of the newborn due to anti-Lan. Transfusion 23, 256–257 (1983).

    Article  CAS  Google Scholar 

  10. Okubo, Y. et al. The rare red cell phenotype Lan negative in Japanese. Transfusion 24, 534–535 (1984).

    Article  CAS  Google Scholar 

  11. Holland, I.B., Cole, S.P.C., Kuchler, K. & Higgins, C.F. ABC Proteins, From Bacteria to Man (Academic Press, New York, 2003).

  12. Paterson, J.K. et al. Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane. Biochemistry 46, 9443–9452 (2007).

    Article  CAS  Google Scholar 

  13. Borst, P. & Elferink, R.O. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71, 537–592 (2002).

    Article  CAS  Google Scholar 

  14. Szakács, G., Paterson, J.K., Ludwig, J.A., Booth-Genthe, C. & Gottesman, M.M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5, 219–234 (2006).

    Article  Google Scholar 

  15. Puy, H., Gouya, L. & Deybach, J.C. Porphyrias. Lancet 375, 924–937 (2010).

    Article  CAS  Google Scholar 

  16. Zhou, S. et al. Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels. Blood 105, 2571–2576 (2005).

    Article  CAS  Google Scholar 

  17. Saison, C. et al. Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior. Nat. Genet. published online (15 January 2012), doi:10.1038/ng.1070.

    Article  CAS  Google Scholar 

  18. Emadi-Konjin, H.P. et al. Isolation of a genomic clone containing the promoter region of the human ATP binding cassette (ABC) transporter, ABCB6. Biochim. Biophys. Acta 1574, 117–130 (2002).

    Article  CAS  Google Scholar 

  19. Ballif, B.A., Carey, G.R., Sunyaev, S.R. & Gygi, S.P. Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain. J. Proteome Res. 7, 311–318 (2008).

    Article  CAS  Google Scholar 

  20. Elias, J.E. & Gygi, S.P. Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat. Methods 4, 207–214 (2007).

    Article  CAS  Google Scholar 

  21. Gouya, L. et al. Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am. J. Hum. Genet. 78, 2–14 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are indebted to all present and past members of the CNRGS for identifying and cryopreserving Lan(−) blood samples. They would like to thank G. Nicolas for his helpful comments on the manuscript. This study was supported in part by the INTS, Inserm and Paris Diderot University (Paris 7). B.A.B. was funded by the Vermont Genetics Network through a grant from the US National Institutes of Health/National Center for Research Resources (P20 RR16462).

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Authors and Affiliations

  1. National Institute of Blood Transfusion (INTS), Paris, France

    Virginie Helias, Carole Saison, Thierry Peyrard, Camille Sureau, Bach-Nga Pham, Pierre-Yves Le Pennec, Jean-Pierre Cartron & Lionel Arnaud

  2. Department of Biology, University of Vermont, Burlington, Vermont, USA

    Bryan A Ballif

  3. National Reference Center for Blood Groups (CNRGS), Paris, France

    Thierry Peyrard, Bach-Nga Pham & Pierre-Yves Le Pennec

  4. Japanese Red Cross Osaka Blood Center, Osaka, Japan

    Junko Takahashi, Hideo Takahashi, Mitsunobu Tanaka & Yoshihiko Tani

  5. Assistance Publique–Hôpitaux de Paris, Centre Français des Porphyries, Institut National de la Santé et de la Recherche Médicale (Inserm), Centre de Recherche Biomédicale Bichat-Beaujon, U 773, Université Paris Diderot–Paris 7, Paris, France

    Jean-Charles Deybach & Hervé Puy

  6. Centre de Recherche des Cordeliers, Inserm, Université Pierre et Marie Curie–Paris 6, Unité Mixte de Recherche (UMR) S 872, Paris, France

    Maude Le Gall

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  1. Virginie Helias
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Contributions

V.H. carried out flow cytometry and protein blot analysis, made expression constructs and performed cell culture. C. Saison performed immunoprecipitation and genomic DNA sequencing. B.A.B. performed mass spectrometry analysis. T.P. provided immunohematological information and most Lan(−) blood samples. J.T., H.T. and M.T. isolated and produced the OSK43 monoclonal antibody. Y.T. conceived and supervised the study at the Japanese Red Cross Osaka Blood Center. H.P. performed porphyrin analysis. M.L.G. performed statistical analysis and provided human cell lines. C. Sureau provided the HuH-7 cell line. B.-N.P. provided two Lan(−) blood samples. P.-Y.L.P. was a former chief operating officer of the CNRGS involved in identifying and cryopreserving Lan(–) blood samples. J.-P.C. initiated the study conducted by L.A. by obtaining OSK43 from Y.T., contacted J.-C.D. for porphyrin analysis and continuously supported the study. L.A. conceived and supervised the study at the INTS, performed experiments, made the figures and wrote the manuscript, which was reviewed by J.-P.C., T.P., M.L.G., H.P., C. Sureau and B.A.B. All authors approved the submitted manuscript.

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Correspondence to Lionel Arnaud.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6 and Supplementary Table 1 (PDF 1469 kb)

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Helias, V., Saison, C., Ballif, B. et al. ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. Nat Genet 44, 170–173 (2012). https://doi.org/10.1038/ng.1069

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