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Mutation of the GATA site in the erythroid cell–specific regulatory element of the ABO gene in a Bm subgroup individual

Authors

  • Tamiko Nakajima,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Rie Sano,

    Corresponding author
    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
    • Address reprint requests to: Rie Sano, Department of Legal Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, 371-8511 Japan; e-mail: takagiri@showa.gunma-u.ac.jp.

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  • Yoichiro Takahashi,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Rieko Kubo,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Keiko Takahashi,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Yoshihiko Kominato,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Junichi Tsukada,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Haruo Takeshita,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Toshihiro Yasuda,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Makoto Uchikawa,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Kazumi Isa,

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • Kenichi Ogasawara

    1. Department of Legal Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
    2. Cancer Chemotherapy Center and Hematology, University of Occupational and Environmental Health, Fukuoka, Japan
    3. Department of Legal Medicine, Shimane University School of Medicine, Shimane, Japan
    4. Division of Medical Genetics and Biochemistry, Faculty of Medicine, University of Fukui, Fukui, Japan
    5. Japanese Red Cross Tokyo Blood Center, Tokyo, Japan
    6. Japanese Red Cross Central Blood Institute, Tokyo, Japan
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  • This work was supported in part by a Grant-in-Aid from Japan Society for the Promotion of Science (21590732 to TN, 23790723 to RS, 22390140 to YK).
  • The nucleotide sequence(s) reported in this paper has been submitted to the GenBank with Accession Numbers JQ765614, JQ765615, JQ765617, and KC427108.

Abstract

Background

The ABO blood group is important in blood transfusion. Recently, an erythroid cell–specific regulatory element has been identified in the first intron of ABO using luciferase reporter assays with K562 cells. The erythroid cell–specific regulatory activity of the element was dependent upon GATA-1 binding. In addition, partial deletion of Intron 1 including the element was observed in genomic DNAs obtained from 111 Bm and ABm individuals, except for one, whereas the deletion was never found among 1005 individuals with the common phenotypes.

Study Design and Methods

In this study, further investigation was performed to reveal the underlying mechanism responsible for reduction of B antigen expression in the exceptional Bm individual. Peptide nucleic acid–clamping polymerase chain reaction was carried out to amplify the B-related allele, followed by sequence determination. Electrophoretic mobility assays and promoter assays were performed to examine whether a nucleotide substitution reduced the binding of a transcription factor and induced loss of function of the element.

Results

Sequence determination revealed one point mutation of the GATA motif in the element. The electrophoretic mobility shift assays showed that the mutation abolished the binding of GATA transcription factors, and the promoter assays demonstrated complete loss of enhancer activity of the element.

Conclusion

These observations suggest that the mutation in the GATA motif of the erythroid-specific regulatory element may diminish the binding of GATA transcription factors and down regulate transcriptional activity of the element on the B allele, leading to reduction of B antigen expression in erythroid lineage cells of the Bm individual.

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