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Large deletions involving the regulatory upstream regions of A4GALT give rise to principally novel P1PK-null alleles

Authors

  • Julia S. Westman,

    1. Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
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  • Åsa Hellberg,

    1. Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
    2. Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories of Region Skåne, Lund, Sweden
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  • Thierry Peyrard,

    1. Institut National de la Transfusion Sanguine, Centre National de Référence pour les Groupes Sanguins, Paris, France
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  • Britt Thuresson,

    1. Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
    2. Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories of Region Skåne, Lund, Sweden
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  • Martin L. Olsson

    Corresponding author
    1. Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
    2. Department of Clinical Immunology and Transfusion Medicine, University and Regional Laboratories of Region Skåne, Lund, Sweden
    • Address reprint requests to: Martin L. Olsson, MD, PhD, Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, SE-221 85 Lund, Sweden; e-mail: Martin_L.Olsson@med.lu.se.

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  • This work was supported by the Swedish Research Council (Project K-2011-14251), governmental research grants (ALF) to the University and Regional Laboratories (Lund, Sweden), and grants from Region Skåne for Research and Development and the Medical Faculty at Lund University, Sweden.

Abstract

Background

Cells of the clinically important p histo-blood group phenotype lack P1, Pk, and P glycosphingolipid antigens. All cases investigated so far are due to alterations in the 4-α-galactosyltransferase-encoding Exon 3 of A4GALT. Repetitive elements in the genome can mediate DNA rearrangements, the most abundant being the Alu family of repeats.

Study Design and Methods

The aim of this study was to determine the genetic basis of three p samples with intact A4GALT open reading frames, using long-range polymerase chain reaction (PCR) and sequencing. In addition, transcript measurements were performed with quantitative PCR.

Results

This is the first report of the p phenotype as the result of large deletions in A4GALT, comprising the proposed promoter and noncoding Exons 1 and 2a. The breakpoints were different in all three samples and revealed the presence of Alu or MIRb sequences directly flanking, or in close proximity to, all junctions. Furthermore, no A4GALT transcripts could be detected.

Conclusion

In summary, our data elucidate a new explanation underlying the p phenotype, implicating the deleted regions of A4GALT as crucial for P1 and Pk synthesis, possibly due to loss of binding sites for erythroid transcription factors. Furthermore, analysis of these regions will improve genetic blood group prediction.

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